Capsule and powder formulations containing lanthanum compounds

ABSTRACT

The present invention includes an oral pharmaceutical capsule comprising a shell, lanthanum carbonate or lanthanum carbonate hydrate, and a lubricant such as talc, wherein the shell encapsulates the lanthanum carbonate or its hydrate and the lubricant. Capsule shells comprise, for example, gelatin. The present invention also includes an oral pharmaceutical powder comprising lanthanum carbonate or lanthanum carbonate hydrate and a pharmaceutically acceptable excipient. The oral pharmaceutical capsules and powders of the present invention can be administered to treat a patient at risk of or suffering from hyperphosphatemia, at risk of or suffering from chronic kidney disease (CKD), at risk of or suffering from soft tissue calcification associated with CKD, or at risk of or suffering from secondary hyperparathyroidism.

This application is a continuation-in-part (CIP) of U.S. applicationSer. No. 12/958,380 filed Dec. 1, 2010 and issued as U.S. Pat. No.8,263,119 on Sep. 11, 2012; the contents of which are incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present invention includes an oral pharmaceutical capsule comprisinga gelatin shell that encapsulates both lanthanum carbonate or lanthanumcarbonate hydrate and a lubricant such as talc. The capsules of thepresent invention dissolve at a similar rate before and after storage.The present invention also includes oral pharmaceutical powderscomprising lanthanum carbonate or lanthanum carbonate hydrate andpharmaceutically acceptable excipients. The powders of the presentinvention possess similar pharmacokinetic properties compared tolanthanum carbonate chewable tablets. The oral pharmaceutical capsulesand powders of the present invention can be administered to treat apatient at risk of or suffering from hyperphosphatemia, at risk of orsuffering from chronic kidney disease (CKD), at risk of or sufferingfrom soft tissue calcification associated with CKD, or at risk of orsuffering from secondary hyperparathyroidism.

BACKGROUND OF THE INVENTION

Hyperphosphatemia is a particular problem of patients with chronic renalinsufficiency or chronic kidney disease (CKD). Approximately 70% ofpatients with end stage renal disease (ESRD) on renal dialysis therapyrequire treatment for hyperphosphatemia. This condition can lead tosevere bone problems and metastatic calcification of skin and majororgans and is associated with significant morbidity and mortality.Conventional dialysis fails to reduce the levels of phosphate in theblood, so that levels rise in time. Elevated phosphate levels aretreated using a combination of dietary restrictions andphosphate-binding agents. Chronic renal insufficiency patients alsosuffer from secondary hyperparathyroidism.

Certain forms of lanthanum carbonate have been used to treathyperphosphatemia in patients with renal failure (see, e.g., JP1876384). U.S. Pat. No. 5,968,976, owned by the assignee of the presentinvention, describes the preparation and use in a pharmaceuticalcomposition of certain hydrates of lanthanum carbonate for the treatmentof hyperphosphatemia. U.S. Pat. Nos. 7,381,428 and 7,465,465, also bothowned by the assignee of the present invention, disclose formulationscontaining lanthanum carbonate and lanthanum carbonate hydrate.

The non-calcium, non-resin phosphate binder lanthanum carbonate as achewable tablet (FOSRENOL®, Shire Pharmaceuticals, Basingstoke, UK) iscommonly used in clinical practice for the reduction of serum phosphorusin patients with CKD Stage 5 who are undergoing dialysis. For patientswho have trouble chewing lanthanum carbonate tablets, who find chewabletablets unpalatable, or who find chewing tablets several times per daytiresome, there is a need in the art for alternative formulationscontaining lanthanum carbonate or lanthanum carbonate hydrate.

SUMMARY OF THE INVENTION

The present invention includes an oral pharmaceutical capsule comprisinga shell that encapsulates both lanthanum carbonate or lanthanumcarbonate hydrate and a lubricant such as talc. The shell of the capsuleincludes, for example, gelatin. The capsules of the present inventiondissolve at a similar rate before and after storage. Capsules caninclude additional encapsulated excipients such as diluents,disintegrants, and flow aids.

The present invention also includes oral pharmaceutical powderscomprising lanthanum carbonate or lanthanum carbonate hydrate andpharmaceutically acceptable excipients. The powders of the presentinvention possess similar pharmacokinetic properties to those oflanthanum carbonate chewable tablets. Powders can include encapsulatedexcipients such as diluents, disintegrants, lubricants, and flow aids.

The oral pharmaceutical capsules and powders of the present inventioncan be administered to treat a patient at risk of or suffering fromhyperphosphatemia. Further uses of the pharmaceutical capsules andpowders include treating a patient (1) at risk of or suffering fromchronic kidney disease (CKD), (2) at risk of or suffering from softtissue calcification associated with chronic kidney disease (CKD), or(3) at risk of or suffering from secondary hyperparathyroidism byadministering the capsules and powders of the invention to the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph comparing the dissolution rates of 3 lanthanumcarbonate capsules (E341x008, E341X010, and 910011) before and afterstorage for 2 weeks at 60° C.

FIG. 2 is a graph comparing the dissolution rates before and afterstorage at 60° C. for 1 week of (1) a formulation that was slugged andencapsulated before storage, (2) a formulation that was not slugged, butencapsulated before storage, and (3) a formulation that was sluggedbefore storage and encapsulated after storage.

FIG. 3 is a graph comparing the dissolution profiles before and afterstorage at 60° C. for 1 week for the following formulations: (1) aformulation without magnesium stearate, (2) a formulation withoutcolloidal silicon dioxide, (3) a formulation containing only lanthanumcarbonate, (4) a formulation without crospovidone, and (5) a formulationwithout dextrates.

FIG. 4 is a graph comparing the dissolution profiles before and afterstorage at 60° C. for 1 week for the following formulations: (1) aformulation containing magnesium stearate, (2) a formulation without alubricant, (3) a formulation containing glycerol behenate instead ofmagnesium stearate, and (4) a formulation containing sodium stearylfumarate instead of magnesium stearate.

FIG. 5 is a graph comparing the dissolution profiles before and afterstorage at 60° C. for 1 week for the following formulations: (1) aformulation containing PEG 6000, (2) a formulation containing L-leucine,(3) a formulation containing L-leucine/PEG 6000, and (4) a formulationcontaining talc.

FIG. 6 is a graph comparing the dissolution profiles before and afterstorage at 60° C. for 1 week for the following formulations: (1) aformulation containing LUBRITAB® and (2) a formulation containingCUTINA® HR.

FIG. 7 is a graph comparing the dissolution profiles before and afterstorage at 60° C. for 1 week for the following formulations: (1) alanthanum carbonate formulation containing only L-leucine and (2) alanthanum carbonate formulation containing dextrates, colloidal silicondioxide, crospovidone, and L-leucine.

FIG. 8 is a graph comparing the dissolution profiles for lanthanumcarbonate capsules containing PEG 6000 before and after storage at 60°C. for 1 week or 50° C. for 1 week.

FIG. 9 is a graph comparing the dissolution profiles for lanthanumcarbonate capsules containing dextrates, colloidal silicon dioxide,crospovidone, and talc before and after storage at 60° C. for 1 or 2weeks and for lanthanum carbonate capsules containing only talc beforeand after storage at 60° C. for 1 week.

FIG. 10 is a graph comparing the dissolution profiles for lanthanumcarbonate capsules containing dextrates, colloidal silicon dioxide,crospovidone, and talc before and after storage at 60° C. for 1 week.

FIG. 11 is a graph showing the arithmetic mean (±SD) plasmaconcentration-time profiles of lanthanum following a final dose (1000mg) of lanthanum carbonate as Regimen A (2×500 mg capsules), Regimen B(2×500 mg opened capsules), or Regimen C (2×500 mg chewable tablets).

FIG. 12 is a graph showing the arithmetic mean (±SD) concentration-timeprofiles for plasma lanthanum for all subjects in the pharmacokineticset following a final dose (1000 mg) of lanthanum carbonate as Regimen A(1000 mg granules) or Regimen B (1000 mg chewable tablets).

DETAILED DESCRIPTION OF THE INVENTION

Capsule and powder formulations provide palatable alternatives tochewable tablets. Like chewable tablets, capsules and powders can beadministered without liquid which is advantageous for patients withkidney disease who must regulate their liquid intake. Capsules can bechewed like a tablet or, for patients who have difficulty chewing,capsules can be opened and the contents can be sprinkled onto the tongueor onto food. Alternatively, capsules can be swallowed whole. Powderscan also be sprinkled onto the tongue or onto food; they do not have tobe chewed and are easy to swallow.

The present invention is based on the unexpected finding that thedissolution rate of lanthanum carbonate in oral pharmaceutical capsules,where the shell encapsulates both lanthanum carbonate hydrate and talc,are unaffected by storage while other encapsulated lubricants cause areduction in the dissolution rate of lanthanum carbonate in capsules, asdemonstrated in the Examples. A consistent dissolution rate before andafter storage is necessary for regulatory approval, provides aconsistent rate and extent of phosphate binding, and allows for greatershelf-life.

The present invention is also based on the unexpected finding thatlanthanum carbonate powder formulations containing dextrates, colloidalsilicon dioxide, crospovidone, and talc were both pharmacodynamicallyand pharmacokinetically equivalent to lanthanum carbonate tabletformulations. Without being bound to any particular theory, this resultis contrary to the hypothesis that a powder formulation may result inmore lanthanum in the blood plasma, compared to a lanthanum carbonatechewable tablet, because the powder may contain more finely groundparticles which have a greater surface area, potentially, leading tofaster dissolution and absorption.

In contrast to the lanthanum carbonate powder formulations describedabove and consistent with the above hypothesis, lanthanum carbonatepowder formulations containing dextrates, colloidal silicon dioxide, andmagnesium stearate were pharmacodynamically equivalent to lanthanumcarbonate tablet formulations, but displayed 30% more lanthanum in theblood plasma compared to tablets. While this increase raises technicalissues which make regulatory approval more difficult, the heightenedamount of lanthanum in the plasma is still within between-studyvariation for the chewable tablet and not considered clinicallysignificant.

Oral Pharmaceutical Powders

Oral pharmaceutical powders include an active ingredient such aslanthanum carbonate or lanthanum carbonate hydrate and one or morepharmaceutically acceptable excipients such as disintegrants,lubricants, diluents, flow aids, or combinations thereof.

The method of making oral powders generally includes optionally sievingthe ingredients, mixing the ingredients, optionally slugging or rollercompacting followed by milling to produce a coarse powder, andoptionally sieving the coarse powder.

For example, lanthanum carbonate hydrate, dextrates, and colloidalsilicon dioxide are sieved into a tumble blender and blended.Crospovidone and talc are sieved into the tumble blender and blendedwith the other ingredients. The blended powder is then passed through aroller compactor and the compacted material is passed through a sieve tomill the material into a free flowing powder.

The powders can then be filled into sachets, stick packs, or rigidcontainers such as glass or plastic bottles or vials either as unitdoses or as bulk quantities from which individual doses can be measuredwith a suitable measuring device using methods known to one of ordinaryskill in the art. Each sachet or stick pack can contain from about 200mg to about 2000 mg of elemental lanthanum as lanthanum carbonate. Forexample, each sachet can contain 250 mg, 500 mg, 750 mg or 1000 mg ofelemental lanthanum as lanthanum carbonate.

Oral Pharmaceutical Capsules

Oral pharmaceutical capsules include a shell that encapsulates an activeingredient such as lanthanum carbonate or lanthanum carbonate hydrate,and other optional ingredients such as a lubricant. The encapsulatedmaterial can be a powder as described above.

A capsule shell can be a hard gel. Hard gel capsule shells typicallyhave a body and a cap. The body and cap materials can comprise a gellingagent and water. The gelling agent can be, but is not limited to,gelatin, modified starch, carrageenan, gellan, mannan gum, amylose,xanthan, alginates, agar, guar, gum arabic, pectin, cyclodextrin or acombination thereof. The shell can optionally include a gelling salt, aplasticizer, an emulsifier, thickener, preservative, flavoring,sweetener, pigment, radiation blocker, opacifying agent, anti-oxidant,masticatory substance, etc.

Gelatin can be manufactured by the partial hydrolysis of collagen fromanimal by-products such as bones, skin, and connective tissue. Bovineand porcine animals are the primary sources of gelatin.

Modified starches, include, for example, non-retrograding starchesderived by chemical modification of starch from any plant source such ascorn, waxy maize, potato, wheat, rice, tapioca, sorghum, etc. Usefulmodified starches are ether and ester derivatives of starch including,for example, hydroxypropyl, hydroxyethyl, succinate, and octenylsuccinate starch derivatives. Other modified starches which may be usedinclude the thermally converted, fluidity or thin boiling type productsderived from the above chemically modified starches. These materials maybe of lower molecular weight, prepared by heating the modified starch,subjecting the starch to hydrolytic acid and/or heat treatment, etc.

Carrageenan is a natural sulfated polysaccharide hydrocolloid derivedfrom seaweed, and is a mixture of galactose and 3-6-anhydrogalactosecopolymers. A number of different carrageenan types exist (e.g., kappa,iota, lambda, etc.) and it is anticipated that any of these may be usedin the present invention.

Gellan gum is an extracellular polysaccharide obtained by aerobicfermentation of the microorganism, Pseudomonas elodea. Various forms ofgellum gum including, but not limited to, native, deacetylated,deacylated clarified, partially deacetylated, partially deacylatedclarified may be used in the present invention.

Mannam gum includes the galactomannan gums, the glucomannan gums andmixtures thereof. Accordingly, mannam gum includes, but is not limitedto, locust bean gum, konjac gum, tara gum and cassia gum.

A gelling salt may be used in the present invention. Accordingly, acalcium salt, a magnesium salt, a barium salt, a sodium salt or apotassium salt of an appropriate inorganic or organic acid may be usedto form the shell of a capsule of the present invention.

Plasticizers can also be added to the shell of a capsule formulation.Plasticizers can be polyols, for example, glycerin, sorbitol, analkylene glycol, maltitol, lactitol, xylitol, corn syrup solids, etc. ora combination thereof.

Pigments can include indigotine (i.e., FD & C Blue 2), erythrosin (i.e.,FD & C Red 3), and titanium dioxide, which also acts as an opacifier.

The body and cap of the capsule shell can comprise between about 10 wt %and 95 wt % gelling agent (e.g., gelatin), between about 75 wt % toabout 95 wt % gelling agent, or between about 80 wt % and 90 wt %gelling agent of the weight of the shell. The body and cap of thecapsule shell can comprise between about 5 wt % and 40 wt % water,between about 5 wt % and about 25 wt % water, or between about 10 wt %and 20 wt % water based on the total weight of the shell. The body andcap of the capsule shell can comprise up to about 10 wt % pigment,between about 0.1 wt % and about 2.5 wt % pigment, or between about 1.5wt % and 2.5 wt % pigment of the weight of the shell.

Capsule shells can be purchased for example from Capsugel® (Peapack,N.J.) and Shionogi Qualicaps® (Whitsett, N.C.). Shells that can be usedto encapsulate lanthanum carbonate formulations can be, for example,Capsugel® Coni-Snap® size 00 for 500 mg capsules and Capsugel®Coni-Snap® 0 el (0 elongated) for 375 mg capsules, where the masses arebased on the mass of elemental lanthanum in the lanthanum carbonate. Thecapsule can be tubular in shape and from about 0.4 inches to about 1.1inches in closed length and from about 0.18 to about 0.4 inches indiameter with a volume of about 0.1 to about 1.4 mL Briefly, capsuleshells are made by dipping rods having dimensions of the cap and body ofthe capsule into a melted, pigmented gelatin solution, allowing the capand body to solidify while rotating the rods to distribute the gelatinevenly, removing the cap and body from the rods, and fitting the cap andbody with each other.

Several methods of producing capsules containing a powder are known inthe art. A powder can be made as discussed in the section describingoral pharmaceutical powders above. The powder is then placed into onehalf of the capsule and the other half of the capsule shell is pressedonto the first half. See Stegemann and Bornem, “Hard gelatin capsulestoday—and tomorrow,” 2^(nd) Edition 2002 from the Capsugel® Library andTousey, “The Granulation Process 101: Basic Technologies for TabletMaking,” Pharmaceutical Technology: Tableting & Granulation 2002, pages8-13.

A capsule can be tested for its stability during storage by storing thecapsule under accelerated aging conditions and testing the capsule forits ability to dissolve before and after storage. Accelerated agingconditions include 25° C., 30° C., 40° C., 50° C., 60° C., 70° C., or80° C. for 1, 2, 3, or 4 weeks or a month optionally at 55%, 60%, 65%,70%, 75%, or 80% relative humidity (RH). These conditions can becorrelated with room temperature conditions using the Arrhenius equationwhich relates rate of reaction (in this case, degradation/instability)to temperature. Conditions can also be internationally recognizedstandard conditions such as 25° C./60% RH, 25° C./65% RH, 30° C./60% RH,30° C./65% RH, 30° C./75% RH, or 40° C./75% RH, 45° C./75% RH for 1, 2,3, or 4 weeks or a month. Capsules before and after storage can becompared by testing their ability to dissolve in solution over time. Forexample as discussed in the Examples, capsules can be exposed to a 0.25M HCl solution and the amount of dissolved lanthanum carbonate orlanthanum carbonate hydrate can be measured over time by titrating thelanthanum in solution with EDTA. The capsules of the present inventioncan be at least 60%, 70%, 80%, 90%, or 100% dissolved (based on, e.g.,the amount of dissolved lanthanum) after 10, 20, 30, 45, or 60 minutesin a solution (e.g., 0.25 M HCl) after the capsules have been exposed toaccelerated aging conditions. For example, the capsules of the presentinvention can be at least 80% dissolved (based on the amount ofdissolved lanthanum) after 30 minutes in 0.25 M HCl after storage at 50°C. or 60° C. for 1 or 2 weeks.

Lanthanum Carbonate and Lanthanum Carbonate Hydrate

“Lanthanum carbonate” as used herein encompasses all hydrated forms oflanthanum carbonate as well as anhydrous lanthanum carbonate.

The capsule and powder formulations of the invention can containlanthanum carbonate having the general formula La₂(CO₃)₃.xH₂O, wherein xhas a value from 0 to 10. Preferably, x has a value from 3 to 8,desirably from 3 to 6. Most preferably, x may have an average value ofabout between 4 and 5. The hydration level of the lanthanum compound canbe measured by methods well known in the art, such as x-ray powderdiffraction (XRPD).

The amount of lanthanum carbonate in the powder or encapsulated in theshell of the capsule ranges from about 50 wt % to about 95 wt %,preferably from about 75 wt % to about 90 wt %, and most preferably fromabout 85 wt % to about 90 wt % based on the total weight of the powderor the contents of the capsule. In one embodiment, the amount oflanthanum carbonate in the powder or encapsulated in the shell of thecapsule is about 87 wt % based on the total weight of the powder or thecontents of the capsule.

The amount of elemental lanthanum as lanthanum carbonate in the powderor encapsulated in the shell of the capsule ranges from about 26 wt % toabout 50 wt %, preferably from about 35 wt % to about 50 wt % and mostpreferably from about 40 wt % to about 50 wt % based on the total weightof the powder or the contents of the capsule. In one embodiment, theamount of elemental lanthanum as lanthanum carbonate in the powder orencapsulated in the shell of the capsule is about 45 wt % based on thetotal weight of the powder or the contents of the capsule.

The amount of elemental lanthanum in a sachet containing the lanthanumcarbonate powder or in the lanthanum carbonate capsule can be 250 mg,350 mg, 500 mg, 750 mg, or 1000 mg and preferably 250 mg, 350 mg, or 500mg.

Additional Ingredients for Encapsulation or for Oral PharmaceuticalPowders

Additional ingredients (i.e., pharmaceutically acceptable excipients)that can be used for oral powders or encapsulated by the shell of acapsule include diluents, lubricants, flow aids, binders, disintegrants,colors, flavors, antioxidant, and sweeteners. The additional ingredientsshould be suitable for oral administration to renally impaired subjects.

A diluent can be added to the formulation in an amount from about 5 wt %to about 50 wt % based on the total weight of the powder or contents ofthe capsule. The total diluent amount can be from about 5 wt % to about30 wt %, preferably from about 5 wt % to about 20 wt %, and mostdesirably from about 5 wt % to about 10 wt % based on the total weightof the powder or capsule contents of the formulation.

Diluents include a monosaccharide, a disaccharide, calcium sulfatedihydrate, an oligosaccharide, isomaltooligosaccharide, erythritol,polydextrose, dextrins, starch, maltodextrin, calcium lactatetrihydrate, microcrystalline cellulose (such as Avicel™ available fromGFS Chemicals (Powell, Ohio)), hydrolyzed cereal solids (such asMaltrons or Mor-Rex™), amylose, or glycine. One or more diluents can bepresent in the formulation.

Suitable monosaccharides for use in the formulation of the presentinvention include, but are not limited to, glyceraldehyde, erythrose,threose, ribose, lyxose, xylose, arabinose, allose, talsoe, gulose,mannose, glucose (e.g., in the form of corn syrup), idose, galactose,altrose, dihydroxyacetone, erythrulose, ribulose, xyloketose, psicose,tagatose, sorbose, fructose, sorbitol, xylitol, inositol, erythritol,and mannitol in either the D- or L-configuration, including derivativesand analogs thereof. Monosaccharides for use in this invention can beeither cyclic (in either alpha- or beta-form) or acyclic and can be usedin the invention as mixtures. Other suitable monosaccharides includedextrose (D-glucose such as Cerelose™ available from Fisher Scientific(Hampton, N.H.)).

Suitable disaccharides for use in the present invention include, but arenot limited to, sucrose (for example, in the form of Di-Pac™ availablefrom Domino Foods in Baltimore, Md., Sugartab™ available from JRS Pharma(Patterson, N.Y.), confectioner's sugar, or Nutab), lactose (includinganhydrous lactose and lactose monohydrate), maltose, isomaltose,cellobiose, trehalose, maltitol (in the form of Lycasin™ available fromRoquette (Lestrem, France)), isomalt, lactitol, mixtures, derivatives,and analogs thereof. Disaccharides of this invention also include anycombination of two monosaccharides linked by a glycosidic bond.Disaccharides can be either homodisaccharides (i.e., consisting of 2monosaccharides that are the same) or heterodisaccharides (i.e.,consisting of 2 monosaccharides that are different). Furthermore,monosaccharides and disaccharides can be used in the same formulation.

Other suitable monosaccharides and disaccharides can be found inRemington: The Science and Practice of Pharmacy (20^(th) Edition, A. R.Gennaro editor, Lippincott Baltimore, Md.: Williams and Wilkins, 2000)at pages 409-413; and in Biochemistry (2^(nd) Edition, Voet and Voet,New York: John Wiley & Sons, Inc., 1995) at pages 251-276. Hydrolyzedstarches containing mono- and/or disaccharides can also be used in theformulations of the invention.

Dextrates can also be used as a monosaccharide/disaccharide diluent. Theterm “dextrates” as used herein refers to a purified mixture ofsaccharides that is mostly dextrose (e.g., not less than about 93.0% andnot more than about 99.0%, calculated on the dried basis) and thatresults from a controlled enzymatic hydrolysis of starch. Dextrates canbe either anhydrous or hydrated. “Dextrates” can refer to dextrates asdefined in the official monograph found in National Formulary 21(printed by Webcom Limited in Toronoto, Canada; 2003). Dextrates areavailable from JRS Pharma (Patterson, N.Y.) as Emdex™.

Useful lubricants can be chosen from, for example, magnesium stearate,talc, mineral oil (liquid paraffin), polyethylene glycol, silica,colloidal anhydrous silica, colloidal silicon dioxide, hydrogenatedvegetable oil, glyceryl behenate, L-leucine, L-leucine/polyethyleneglycol 6000, polyethylene glycol 6000 or glyceryl monostearate. Usefulflow aids can be chosen from, for example, silica, colloidal anhydroussilica, or colloidal silicon dioxide. Generally, lubricants stop aformulation from sticking to the process equipment while flow aidsenable the formulation to flow freely while being processed. Oneingredient can be both a lubricant and a flow aid. One or morelubricants can be present in a formulation. One or more flow aids can bepresent in a formulation. In one embodiment, the lubricant can be talcand the flow aid can be colloidal silicon dioxide.

The lubricant amount can be from about 0.01% to about 0.05%, preferablyfrom about 0.01% to about 0.04%, and most desirably from about 0.01% toabout 0.03% by weight of the powder or the capsule contents of theformulation. The flow aid amount can be from about 0.1% to about 4%,preferably from about 0.1% to about 3%, and most desirably from about0.1% to about 2% by weight of the powder or the capsule contents of theformulation.

Disintegrants can be chosen from crospovidone, croscarmellose sodium,starches such as sodium starch glycolate and pregelatinized cornstarches, clays, celluloses such as purified cellulose, microcrystallinecellulose, methylcellulose, carboxymethylcellulose and sodiumcarboxymethylcellulose, alginates, and gums such as agar, guar, locustbean, karaya, pectin and tragacanth gums. One or more disintegrants canbe present in a formulation. The total disintegrant amount can be fromabout 1.0 wt % to about 15 wt %, preferably from about 3 wt % to about10 wt %, and most desirably from about 3 wt % to about 5 wt % by weightof the powder or the capsule contents of the formulation.

Combination Therapies

Lanthanum carbonate powders and capsules can be administered withvitamin D, a calcium source, vitamin K, or a combination thereof. Theseadditional ingredients can be mixed with the lanthanum carbonate oradministered separately.

Often, a subject suffering from hyperphosphatemia or the symptoms of CKDis vitamin D deficient. Levels of 25-hydroxy vitamin D₂ are low atvalues less than about 16 ng/mL and replacement treatment aims forlevels of greater than or equal to about 16 ng/mL. Levels of 1,25-dihydroxy vitamin D₂ are low at values less than about 22 pg/mL andreplacement treatment aims for levels of greater than about 22 pg/mL.Thus, it becomes desirable to produce and administer to a patient aformulation containing lanthanum carbonate and vitamin D or an analog ofvitamin D or to administer to a patient a separate formulationcontaining lanthanum carbonate and a separate formulation containingvitamin D or an analog of vitamin D.

Examples of vitamin D sources which may be used include 1,25dihydroxy-vitamin D, the active metabolite of vitamin D (calcitriol,rocalcitrol). Examples of suitable vitamin D analogs includedoxercalciferol (Hectorol™, available from Genzyme, Cambridge, Mass.)and paricalcitol (Zemplar™, available from Abbott Laboratories, AbbottPark, Ill.). One or more vitamin D sources or vitamin D analogs can bepresent in a formulation.

When Vitamin D is administered in a separate dosage form, vitamin D canbe administered once per day to a patient requiring treatment.

Hyperphosphatemic subjects or subjects having symptoms of CKD oftensuffer from hypocalcaemia (i.e., a blood calcium concentration belowabout 8.5 mg/dL). Hence, a formulation of the invention can includelanthanum carbonate and a calcium source.

Examples of forms of calcium include calcium carbonate (e.g., Tums™available from GlaxoSmithKline, Uxbridge, UK), calcium acetate (e.g.,PhosLo™ available from Fresenius, Waltham, Mass.), and CaCl₂. One ormore calcium sources can be present in a formulation.

A calcium source can also be administered in a separate dosage form and,in some instances, concurrently with a dosage form of this invention. Ina specific embodiment, 1-2 tablets containing calcium are given 1-3times per day to a patient requiring treatment.

A subject suffering from hyperphosphatemia or the symptoms of CKD can bevitamin K deficient. In another embodiment of the present invention, theformulation of the invention, in combination with vitamin K, isadministered to a subject suffering from hyperphosphatemia or thesymptoms of CKD to alleviate vitamin K deficiency. Examples of vitamin Ksources include vitamin K1 (phylloquinone), vitamin K2 (menaquinone),and vitamin K3 (menadione).

Vitamin K can be combined in the same formulation as the lanthanumformulation or can be given in a different formulation. In a specificembodiment, 2.5 to 25 mg of vitamin K1 are administered once per day toa subject requiring treatment.

Treatment Methods

Subjects susceptible to or suffering from hyperphosphatemia, at risk ofchronic kidney disease (CKD), having stage one to five CKD, susceptibleto or suffering from soft tissue calcification associated with CKD,susceptible to or suffering from secondary hyperparathyroidism, orsusceptible to or suffering from other as yet undiscovered conditionsrequiring control of phosphate absorption, can be treated byadministering a therapeutically effective amount of a lanthanumcarbonate powder or capsule formulation of the present invention.

As used herein, the terms “treat,” “treating,” or “treatment” mean theprevention, reduction, amelioration, partial or complete alleviation, orcure of hyperphosphatemia, chronic kidney disease (CKD), severe boneproblems, soft tissue calcification, secondary hyperparathyroidism, orother as yet undiscovered conditions requiring control of phosphateabsorption.

Further, as used herein, the term “subject” refers to a mammal (e.g.,any veterinary medicine patient such as a domesticated animal, such as adog or cat), or a human patient.

A “pharmaceutically effective amount” or “therapeutically effectiveamount” as used herein is an amount or dose of lanthanum carbonatesufficient (i) to detectably decrease the serum phosphate levels of asubject or (ii) at a minimum, to keep the serum phosphate levels of asubject substantially constant.

The term “symptom(s)” of those at risk of or having hyperphosphatemia,CKD, soft tissue calcification associated with CKD, or secondaryhyperparathyroidism may be any functional or structural abnormalityexperienced by a subject and indicating kidney dysfunction. Among otherabnormalities, as an example, one or more of the following symptoms mayindicate risk for or the presence of CKD: a serum creatinineconcentration above the normal range for body weight and muscle mass, ablood phosphate level of above about 4.5 mg/dL, any detectable amount ofblood from the kidneys in the urine, a protein to creatinine ratio ofgreater than 0.3 mg/mg, an albumin to creatinine ratio of greater than30 mg/g, an intact parathyroid hormone (PTH) concentration in the bloodof above about 150 pg/mL (second generation parathyroid hormone assay),or a glomerular filtration rate (GFR) of below about 90 mL/min/1.73 m².

Subjects susceptible to or suffering from hyperphosphatemia can betreated by administering a therapeutically effective amount of alanthanum carbonate formulation of the invention.

Hyperphosphatemia as used herein refers to a condition of a patienthaving blood phosphate levels of above about 4.5 mg/dL.

The National Kidney Foundation-Kidney Disease Outcomes QualityInitiative (“NKF-K/DOQI” or “K/DOQI,” as referred to herein) has definedchronic kidney disease (CKD) as either (1) having kidney damage asdefined by structural or functional abnormalities of the kidney for 3months or longer with or without a decreased glomerular filtration rate(GFR) or (2) having a GFR of less than 60 mL/min/1.73 m² for 3 months orlonger with or without kidney damage. Structural or functionalabnormalities are manifested by symptoms such as either pathologicabnormalities or markers of kidney damage, including abnormalitiesidentified in imaging studies or the composition of blood or urine.

Examples of markers of kidney damage include a plasma creatinineconcentration of above the normal range for body weight and muscle mass,Additional markers of kidney damage can include hematuria (i.e., anydetectable amount of blood from the kidneys in the urine), proteinuria(i.e., a protein to creatinine ratio of greater than 0.3 mg/mg),albuminuria (i.e., an albumin to creatinine ratio of greater than 30mg/g), an intact parathyroid hormone (PTH) concentration in the bloodabove about 150 pg/mL (second generation parathyroid hormone assay), orblood phosphate levels of above about 4.5 mg/dL. One specific marker ofkidney disease is a GFR rate below normal (i.e., a GFR below about 90mL/min/1.73 m²).

K/DOQI has published guidelines that define five different stages of CKD(Am J Kidney Dis. 2001, 37(suppl 1):S1-S238). The following tableprovides a description of each of the five stages of CKD and the GFRranges for each of the stages.

TABLE 1 Five Stages of Chronic Kidney Disease (CKD) GFR (mL/min/1.73 m²)Description 90-120 (with CKD Stage At risk symptoms) 1 Kidney damagewith normal or ≧90 elevated GFR 2 Kidney damage with mildly 60-89reduced GFR 3 Moderately reduced GFR 30-59 4 Severely reduced GFR 15-295 Kidney Failure (ESRD) <15 (or dialysis)

Hyperphosphatemia in CKD subjects has several secondary effects. When asubject suffers from hyperphosphatemia, excess serum phosphate canprecipitate serum calcium causing widespread ectopic extraskeletalcalcification. Unwanted calcium deposits can occur in cardiovasculartissue, resulting in an increased risk of cardiovascular complicationsthat often lead to death. Additionally, increased serum phosphateindirectly decreases intestinal calcium absorption. These two mechanismswork concurrently to reduce serum calcium levels.

A reduction in serum calcium levels can contribute to an increase in theproduction of parathyroid hormone (PTH) with the development ofsecondary hyperparathyroidism. Furthermore, recent studies show thathigh phosphate levels can stimulate PTH production directly and lead tosecondary hyperparathyroidism. Continual stimulation of PTH secretioninduces hyperplasia of the parathyroid gland that eventually could leadto a parathyroidectomy becoming necessary.

It is believed that the method of the present invention involving theadministration of a lanthanum carbonate powder or capsule formulationnot only reduces plasma phosphate levels but ameliorates the effects ofCKD in subjects susceptible to or having any of stages one to five CKD,including hyperphosphatemia, ectopic extraskeletal calcification, serumhypocalcemia, and secondary hyperparathyroidism. It should however, beunderstood that this invention is not limited to any particularbiochemical or physiological mechanism.

A subject having a symptom or symptoms of chronic kidney disease (CKD)can be treated by administering to the subject a therapeuticallyeffective amount of a lanthanum carbonate powder or capsule formulationof the present application. The subject treated may be at risk of CKD orhave any of stages one to five CKD. Subjects at risk of CKD or who haveany of stages one to five CKD who may be treated may have one or more ofthe following symptoms: a blood phosphate level of above about 4.5mg/dL, a plasma creatinine concentration above the normal range for bodyweight and muscle mass, any detectable amount of blood from the kidneysin the urine, a protein to creatinine ratio of greater than 0.3 mg/mg,an albumin to creatinine ratio of greater than 30 mg/g, an intactparathyroid hormone concentration in the blood above about 150 pg/mL(second generation parathyroid hormone assay), an abnormal GFR, orcombination thereof.

A subject having a symptom or symptoms of CKD can be treated forcalcification of soft tissue associated with CKD by administering to thesubject a therapeutically effective amount of a lanthanum carbonatepowder or capsule formulation of the present invention. Calcificationcan occur in any soft tissue. Soft tissue can include arterial tissue,cardiac muscle, heart valves, joints, skin and breast tissue.

A subject suffering from or having one or more symptoms of secondaryhyperparathyroidism can be treated in part by administering to thesubject a therapeutically effective amount of a lanthanum carbonatepowder or capsule formulation of the present application.Hyperparathyroidism is defined as a disease in a subject having anintact PTH level of about 150 pg/mL or greater (second generationparathyroid hormone assay). The symptoms of late stagehyperparathyroidism include hypocalcaemia (i.e., a blood calcium levelbelow about 8.5 mg/dL), hyperphosphatemia (i.e., a blood phosphate levelof above about 4.5 mg/dL), and bone disorders (e.g., bone fractures orbone pain).

Administration of Pharmaceutical Powder and Capsules

The lanthanum carbonate powder and capsule formulations can be orallyadministered to subjects in accordance with this invention in dosageforms varying from about 125 to about 2000 mg elemental lanthanum aslanthanum carbonate with or immediately after meals. A typical dosagefor an adult can be, e.g., 375 mg-6000 mg elemental lanthanum aslanthanum carbonate daily. More preferably, the dosage is 375-3750mg/day. The dose can be divided and taken with each meal, for example a250, 500, 750, or 1000 mg sachet or a 250, 375, or 500 mg capsule, e.g.,three times per day. Serum phosphate levels can be monitored weekly anddosages can be modified until an optimal serum phosphate level isreached. Administration may be conducted in an uninterrupted regimen;such a regimen may be a long term regimen, e.g., a permanent regimen,for treating chronic conditions. Capsules can be chewed like a tabletor, for patients who have difficulty chewing, capsules can be opened andthe contents can be sprinkled onto the tongue or onto food.Alternatively, capsules can be swallowed whole. Powders can also besprinkled onto the tongue or onto food or mixed with small amounts ofwater or soft drinks.

The bioavailability (percentage of the dose absorbed unchanged into theplasma) of lanthanum after administration of a formulation is very low(i.e., approximately 0.001%), corresponding to average maximum plasmaconcentrations (C_(max)) of up to approximately 0.7 ng/mL and averageAUC (area under the plasma concentration-time curve) of up toapproximately 24 ng·h/mL in healthy volunteers at steady state aftertypical doses of 1000 mg tid administered by lanthanum carbonatechewable tablets, with corresponding values in dialysis patients beingapproximately 1.1 ng/mL and approximately 31 ng·h/mL, respectively).Typically, T_(max) (time of first achievement of C_(max)) values areessentially unaffected by dose and C_(max) and AUC values vary linearlywith dosage for oral dosages up to about 1500 mg/day. Typically, C_(max)and AUC values plateau for dosages above about 1500 mg/day. As plasmaconcentrations of lanthanum are a surrogate safety marker, an alternateformulation should deliver plasma lanthanum concentrations which are nothigher, substantially or to a clinically significant extent, than thoseachieved with comparable doses of the chewable tablet formulation.

It will be understood that the type of lanthanum carbonate formulationand the duration of the treatment will vary depending on therequirements for treatment of individual subjects. The precise dosageregimen will be determined by the attending physician or veterinarianwho will, inter alia, consider factors such as body weight, age andspecific symptoms. The physician or veterinarian may titrate the dosageof lanthanum carbonate administered to a subject to determine thecorrect dosage for treatment. For example, a physician can measurephosphate levels in a patient, prescribe a particular lanthanumcarbonate dosage to the patient for a week, and evaluate after the weekif the dosage is appropriate by remeasuring phosphate levels in thepatient.

EXAMPLES Examples 1-12 Compatibility Studies of 500 mg LanthanumCarbonate Hydrate Immediate Release Capsules

Lanthanum carbonate hydrate immediate release capsules were studied todetermine their dissolution properties and to ensure that dissolutionwas unaffected after storage.

Examples 1-3 examine the cause of the decreased dissolution observedafter storage of lanthanum carbonate capsules. Based on theseexperiments it was hypothesized that the gelatin of the capsule shelland the encapsulated magnesium stearate caused the decreaseddissolution. Alternative lubricants to magnesium stearate were evaluatedin place of magnesium stearate. Examples 4-9, 11, and 12 examine thedissolution properties of capsules containing alternative lubricants toreplace magnesium stearate. Example 10 discloses the process for makingthe capsules tested in Examples 11 and 12.

Examples 1-9, 11, and 12 below each used the following dissolutionmethod for determining the dissolution rate for lanthanum carbonatecontained in 500 mg lanthanum carbonate hydrate immediate releasecapsules.

Preparation of Solutions

Preparation of Dissolution Medium (0.25 M HCl)

For the preparation of 10 liters of 0.25 M HCl, 232.5 mL of HCl 37%(available from Merck, Darmstadt, Germany) was transferred into a 10 Lvolumetric flask and filled to volume using deionized water. The volumewas scaled depending on requirements.

Urotropin Solvent (1 mol/L) (Hexamine)

35.0 g urotropin (hexamethylenetetramine) (available from VWR, WestChester, Pa.) was dissolved in a 250 mL volumetric flask filled tovolume with purified water.

Sodium Acetate Buffer pH 6.2 (0.2 mol/L)

16.4 g sodium acetate (available from Merck, Darmstadt, Germany) wasdissolved in a 1000 mL volumetric flask filled to volume with purifiedwater and adjusted to pH 6.2 with acetic acid (available from Merck,Darmstadt, Germany).

Xylenol Orange Indicator Solution

10 mg Xylenol orange tetra sodium salt (available from Merck, Darmstadt,Germany) was dissolved in 5 mL ethanol (available from Merck, Darmstadt,Germany) in a 10 mL volumetric flask and diluted to volume usingpurified water. The solution expired after 1 week.

Disodium EDTA (0.001 mol/L) Volumetric Standard Solution

The volumetric standard solution was prepared using a 1/10 volumetricdilution of commercially available standardized 0.01 mol/L EDTA(available from Fluka/Sigma Aldrich, St. Louis, Mo.).

Measuring Capsule Dissolution Over Time

A Sotax AT7 Smart (available from Sotax, Hopkinton, Mass.) with 6×900 mLdissolution vessels, 6 corresponding paddles (USP Type II at 50 rpm),and a Whatman GF/D (2.7 μm glass fiber) filter that complied with USPApparatus 2 and JP Method 2 requirements were used to perform thedissolution. 900 mL of dissolution medium was allowed to equilibrate forat least 30 min in a dissolution bath at 37° C.±0.5° C. One capsule wasthen dropped into the dissolution medium. 15 mL of the medium wasremoved after 5, 10, 15, 30, and 45 minutes using an automatic fractioncollector. 15 mL 0.025 M HCL replaced the removed medium at each timepoint.

To determine the amount of lanthanum ion in the sample, 40 mL of 0.2mol/L sodium acetate solution pH 6.2 was added to 2.5 mL of removedmedium. 0.25 mL of xylenol orange indicator solution was then added andthe pH was adjusted to 5.5±0.1 using 1 mol/L hexamine or 0.25 mol/L HCL.The sample was then titrated using 0.001 mol/L disodium EDTA solutionfrom a pink/lilac starting color to a straw color end point. The amountof EDTA solution was correlated to an amount of lanthanum ion in themedium. Lanthanum(III) oxide (La₂O₃) (Fluka 04052 available from SigmaAldrich, St. Louis, Mo.) was used as a reference standard for the amountof lanthanum ion in solution in the titration analysis. Two or threecapsules per formulation and condition were generally tested. It wasclear from early studies that such small numbers of capsules couldreliably show if dissolution rate was affected by the experimentalvariables under test.

Making the Capsule Formulations Tested in Examples 1-9

Prior to mixing, the ingredients were sieved with a 1.00 mm sieve. Thelanthanum carbonate, dextrates (when present), and disintegrant (whenpresent) were mixed for 10 minutes. The colloidal silicon dioxide (whenpresent) was then added and mixed for 2 minutes. Lubricant (whenpresent) was added and mixed for a further 2 minutes. After slugging toobtain a large tablet or roller compacting, the mixture was milled intoa coarser powder with better flow properties than the original powdersfrom which the slugs were made. (Unless otherwise stated, the mixturewas slugged prior to milling.) The mixture was then sieved again with a1.00 mm sieve.

Hard gelatin capsules were then filled with the lanthanum carbonatepowders in an amount equal to 500 mg elemental lanthanum per capsules.Capsugel® (Peapack, N.J.) supplied Coni-Snap® hard gelatin capsules size00 (0.95 mL volume; 0.917 inches closed length) having the belowcomposition to encapsulate the lanthanum carbonate powders. The body ofthe capsule shell contained 2 wt % titanium dioxide, 13-16 wt % water,and 82-85 wt % gelatin. The cap of the capsule shell contained 0.1779 wt% indigotine (i.e., FD & C Blue 2), 0.171 wt % erythrosin (i.e., FD & CRed 3), 1.4779 wt % titanium dioxide, 13-16 wt % water, and theremainder being gelatin.

Example 1 Dissolution Profiles for Lanthanum Carbonate Capsules Storedat 60° C. for 2 Weeks

Three batches of lanthanum carbonate capsules were manufactured: (1)900911 made via roller compaction, (2) E341X010, a batch with the sameformula as 900911 but made via slugging, and (3) E341X008, a batch madevia slugging with crosscarmellose sodium as disintegrant in place ofcrospovidone.

The dissolution profiles for 3 capsules (E341X008, E341X010, and 910011,number of samples n=2) were determined before and after storage in adrying oven at 60° C. for 2 weeks as shown in FIG. 1. The formulationfor each of the 3 capsules is shown in Table 2.

TABLE 2 Formulations tested for their dissolution profiles before andafter storage at 60° C. for 2 weeks. Formulation E341X008 FormulationE341X010 Formulation 910011 Name mg/dosi Name mg/dosi Name mg/dosiLanthanum carbonate 954.0 Lanthanum carbonate 954.0 Lanthanum carbonate954.0 Dextrates 87.7 Dextrates 87.7 Dextrates 87.7 Colloidal silicon11.0 Colloidal silicon 11.0 Colloidal silicon 11.0 dioxide (Aerosil ®200) dioxide (Aerosil ® 200) dioxide (Aerosil ® 200) Croscarmellose 44.0Crospovidone 44.0 Crospovidone 44.0 Sodium Magnesium stearate 3.3Magnesium stearate 3.3 Magnesium stearate 3.3

As shown in FIG. 1, the dissolution profiles for all capsules afterstorage at 60° C. for 2 weeks showed a delayed release with a 10 minuteslag time and a lanthanum carbonate dissolution of 35-55% after 45minutes. Unstressed samples demonstrated a greater than 90% lanthanumcarbonate dissolution after 30 minutes.

Capsules from batch number 900911 were also stored for one month at 25°C./60% RH, 30° C./60% RH and 45° C./75% RH. The dissolution rates of thestored capsules at all storage conditions decreased compared to prior tostorage. The capsules after storage were less than 80% dissolved after30 minutes.

Example 2 Dissolution Profiles for Compacted (i.e., Slugged) andEncapsulated Lanthanum Carbonate

TABLE 3 Formulation for testing preparation methods Formulation E341X018Name mg/dosi Lanthanum carbonate 954.0 Dextrates 87.7 Colloidal silicondioxide 11.0 (Aerosil ® 200) Crospovidone 44.0 Magnesium stearate 3.3

To determine whether slugging or encapsulation affected dissolutionrates, three different preparations based on formulation batch E341X018(Table 3) were produced: (1) a formulation that was slugged andencapsulated prior to storage, (2) a formulation that was not slugged,but encapsulated prior to storage, and (3) a formulation that wasslugged prior to storage and encapsulated after storage. The threepreparations before and after storage in a drying oven at 60° C. for 1week were tested for their dissolution properties (number of samplesn=3). The dissolution profiles for the preparations before and afterstorage are displayed in FIG. 2.

Although storage delayed dissolution of each of the preparationscompared to before storage, the slugged, unencapsulated prior to storagepreparation was less affected by storage than the slugged, encapsulatedpreparation and the unslugged, encapsulated preparation. These resultssuggest that the gelatin capsule shell may contribute to the decreaseddissolution rate.

Example 3 Impact of a Single Ingredient on the Dissolution Profile ofLanthanum Carbonate Capsules

To determine whether a single ingredient in the capsule formulationaffected dissolution rates, the dissolution profiles of formulationsmissing a single ingredient before and after storage in a drying oven at60° C. for 1 week were determined. The base formulation, prior toremoval of ingredients, is shown in Table 4.

TABLE 4 Base formulation prior to removal of ingredients BasisFormulation Name mg/dosi Lanthanum carbonate 954.0 Dextrates 87.7Colloidal silicon dioxide 11.0 (Aerosil ® 200) Crospovidone 44.0Magnesium stearate 3.3

FIG. 3 provides the dissolution profiles before and after storage forthe following formulations: (1) a formulation without magnesiumstearate, (2) a formulation without colloidal silicon dioxide, (3) aformulation containing only lanthanum carbonate, (4) a formulationwithout crospovidone, and (5) a formulation without dextrates.

Formulations without magnesium stearate both prior to and after storageshowed relatively fast dissolutions. The dissolution curves forformulations containing only lanthanum carbonate before and afterstorage were overlapping. Formulations without dextrates showed adelayed release profile with a lag of 5 minutes both before and afterstorage. Formulations without colloidal silicon dioxide and formulationswithout crospovidone both demonstrated a delayed release dissolutionprofile with a lag of 5 minutes prior to storage and a delayed releasedissolution profile with a lag of 10 minutes after storage. All theformulations containing magnesium stearate had reduced dissolution ratesafter storage and it was deduced that the presence of magnesium stearateand the gelatin capsule shell were together responsible for thereduction in dissolution rate during storage.

Example 4 Dissolution Profiles for Lanthanum Carbonate CapsulesContaining Magnesium Stearate, Glycerol Behenate, or Sodium StearylFumarate

Alternative lubricants were tested to determine their effect on thedissolution of lanthanum carbonate capsules before and after storage. Asshown in Table 5, 4 formulations were tested: (1) a formulationcontaining magnesium stearate, (2) a formulation without a lubricant,(3) a formulation containing glycerol behenate instead of magnesiumstearate, and (4) a formulation containing sodium stearyl fumarateinstead of magnesium stearate.

TABLE 5 Formulations tested for their dissolution profiles before andafter storage in a drying oven at 60° C. for 1 week. FormulationE341X018 Formulation E341X019 Name mg/dosi Name mg/dosi Lanthanumcarbonate 954.0 Lanthanum carbonate 1908.0 Dextrates 87.7 Dextrates 87.7Colloidal silicon dioxide 11.0 Colloidal silicon dioxide 11.0 (Aerosil ®200) (Aerosil ® 200) Crospovidone 44.0 Crospovidone 44.0 Magnesiumstearate 3.3 Magnesium stearate 0.0 Formulation E341X023 FormulationE341X024 Name mg/dosi Name mg/dosi Lanthanum carbonate 954.0 Lanthanumcarbonate 954.0 Dextrates 76.7 Dextrates 76.7 Colloidal silicon dioxide11.0 Colloidal silicon dioxide 11.0 (Aerosil ® 200) (Aerosil ® 200)Crospovidone 44.0 Crospovidone 44.0 Glycerol behenate 11.0 Sodiumstearyl fumarate 11.0

FIG. 4 discloses the dissolution curves for formulations containingdifferent lubricants before and after storage in a drying oven at 60° C.for 1 week. Formulations containing magnesium stearate and formulationscontaining glycerol behenate had relatively fast dissolution profilesprior to storage and delayed release dissolution profiles with a lag of5 minutes after storage. Formulations without a lubricant dissolvedrelatively fast both before and after storage. Formulations containingsodium stearyl fumarate had a delayed release dissolution profile with alag of 5 minutes before storage and a delayed release dissolutionprofile with a lag of 10 minutes after storage.

Example 5 Dissolution Profiles for Lanthanum Carbonate CapsulesContaining PEG 6000, L-Leucine, L-Leucine/PEG 6000, or Talc

Alternative lubricants were tested to determine their effect on thedissolution of lanthanum carbonate capsules before and after storage ina drying oven at 60° C. for 1 week. As shown in Table 6, 4 formulationswere tested each with a different lubricant: polyethyleneglycol,L-leucine, L-leucine/PEG 6000, or talc. The L-leucine/PEG 6000 lubricantis a mixture of 60 wt % L-leucine (available from Sigma-Aldrich, St.Louis, Mo.) and 40 wt % PEG 6000 (available from Croda, East Yorkshire,UK).

TABLE 6 Formulations tested for their dissolution profiles before andafter storage at 60° C. for 1 week. Formulations Name mg/dosi Lanthanumcarbonate 954.0 Dextrates 0.0 Colloidal silicon dioxide (Aerosil ® 200)0.0 Crospovidone 0.0 PEG 6000, L-leucine, L-leucine/PEG 6000, or 55.0talc

FIG. 5 discloses the dissolution curves for formulations containingdifferent lubricants before and after storage in a drying oven at 60° C.for 1 week. Formulations containing PEG 6000 had a relatively fastdissolution profile prior to storage and showed no significant releaseafter storage. Formulations containing L-leucine and formulationscontaining a mixture of L-leucine and PEG 6000 had a relatively fastdissolution profile prior to storage and showed a delayed release with alag of 5 minutes after storage. Formulations containing talc hadrelatively fast dissolution profiles both before and after storage.

Example 6 Dissolution Profiles for Lanthanum Carbonate CapsulesContaining LUBRITAB® or CUTINA® HR

Alternative lubricants were tested to determine their affect on thedissolution of lanthanum carbonate capsules before and after storage ina drying oven at 60° C. for 1 week. As shown in Table 7, 2 formulationswere tested each with a different lubricant: LUBRITAB® (hydrogenatedvegetable oil and hydrogenated oil; available from J. Rettenmaier &Söhne GMBH+CO.KG, Rosenberg, Germany) or CUTINA® HR (hydrogenated castoroil; available from Cognis, Cincinnati, Ohio).

TABLE 7 Formulations tested for their dissolution profiles before andafter storage at 60° C. for 1 week. Formulations Name mg/dosi Lanthanumcarbonate 954.0 Dextrates 0.0 Colloidal silicon dioxide (Aerosil ® 200)0.0 Crospovidone 0.0 LUBRITAB ® or CUTINA ® HR 55.0

FIG. 6 discloses the dissolution curves for formulations containingdifferent lubricants before and after storage at 60° C. for 1 week.Formulations containing LUBRITAB® had a delayed release profile with alag of 5 minutes before and after storage although storage caused a moredelayed release over time. Formulations containing CUTINA® HR testedbefore and after storage had similar delayed release profiles with a lagof 10 minutes.

Example 7 Dissolution Profiles for Lanthanum Carbonate CapsulesContaining Either Dextrates, Colloidal Silicon Dioxide, Crospovidone,and L-Leucine or Only L-Leucine

Lanthanum carbonate capsules containing either dextrates, colloidalsilicon dioxide, crospovidone, and L-leucine or only L-leucine weretested to determine their affect on the dissolution of lanthanumcarbonate capsules before and after storage in a drying oven at 60° C.for 1 week. As shown in Table 8, 2 formulations were tested.

TABLE 8 Formulations tested for their dissolution profiles before andafter storage at 60° C. for 1 week. Formulation E341X030 FormulationE341X031 Name mg/dosi Name mg/dosi Lanthanum carbonate 954.0 Lanthanumcarbonate 954.0 Dextrates 0.0 Dextrates 36.0 Colloidal silicon dioxide0.0 Colloidal silicon dioxide 11.0 (Aerosil ® 200) (Aerosil ® 200)Crospovidone 0.0 Crospovidone 44.0 L-Leucine 55.0 L-Leucine 55.0

FIG. 7 discloses the dissolution curves for the 2 formulations beforeand after storage at 60° C. for 1 week. Lanthanum carbonate formulationscontaining only L-leucine had a relatively fast release profile beforestorage and had a delayed release profile with a lag of 5 minutes afterstorage. Lanthanum carbonate formulations containing dextrates,colloidal silicon dioxide, crospovidone, and L-leucine after storagereleased at a slower rate compared to before storage.

Example 8 Dissolution Profiles for Lanthanum Carbonate CapsulesContaining PEG 6000 Before and after Storage at 60° C. for 1 Week or 50°C. for 1 Week

Lanthanum carbonate capsules containing PEG 6000 were tested todetermine their dissolution before and after storage at 60° C. for 1week or 50° C. for 1 week. As shown in Table 9, the followingformulation was tested.

TABLE 9 Formulation tested for its dissolution profiles before and afterstorage at 60° C. for 1 week or 50° C. for 1 week. Formulations Namemg/dosi Lanthanum carbonate 954.0 Dextrates 0.0 Colloidal silicondioxide (Aerosil ® 200) 0.0 Crospovidone 0.0 PEG 6000 55.0

FIG. 8 discloses the dissolution curves for the formulation before andafter storage at 60° C. for 1 week or 50° C. for 1 week. Testing at 50°C. was performed since the melting point of PEG 6000 is 55° C.Formulations prior to storage showed a relatively fast dissolutionprofile. Formulations after storage at 50° C. for 1 week showed adelayed release with a lag of 5 minutes while formulations after storageat 60° C. for 1 week showed no significant release.

Example 9 Dissolution Profiles for Lanthanum Carbonate CapsulesContaining Either Dextrates, Colloidal Silicon Dioxide, Crospovidone,and Talc or Only Talc

Lanthanum carbonate capsules containing dextrates, colloidal silicondioxide, crospovidone, and talc were tested to determine theirdissolution before and after storage in a drying oven at 60° C. for 1 or2 weeks. Lanthanum carbonate capsules containing only talc were testedto determine their dissolution before and after storage at 60° C. for 1week. As shown in Table 10, the following formulations were tested.

TABLE 10 Formulations tested for their dissolution profiles before andafter storage at 60° C. for 1 or 2 weeks. Formulation E341X034Formulation E341X035 Name mg/dosi Name mg/dosi Lanthanum carbonate 954.0Lanthanum carbonate 954.0 Dextrates 0.0 Dextrates 36.0 Colloidal silicondioxide 0.0 Colloidal silicon dioxide 11.0 (Aerosil ® 200) (Aerosil ®200) Crospovidone 0.0 Crospovidone 44.0 Talc 55.0 Talc 55.0

FIG. 9 discloses the dissolution curves for the formulations before andafter storage at 60° C. for 1 or 2 weeks. All formulations prior to andafter storage provided relatively fast dissolution profiles. Talc is atemperature stable lubricant for lanthanum carbonate capsules.

Example 10 Manufacturing of Lanthanum Carbonate Capsules Containing Talc

TABLE 11 Ingredients for the Lanthanum Carbonate Capsule Ingredientbatch amount % (wt/wt) Lanthanum carbonate 1845634 954.0 mg  86.7Dextrates (Emdex ®) 474620 90.7 mg 8.2 Colloidal silicon dioxide(Aerosil ® 1926183 11.0 mg 1.0 200) Crospovidone 2200764 44.0 mg 4.0Talc 1910860 0.275 mg  0.025

The ingredients in Table 11 were weighed to a batch size of 104.5 kg andsieved with a 1 mm hand sieve. Lanthanum carbonate, dextrates andcrospovidone were then blended for 10 min on a tumble blender. Thecolloidal silicon dioxide was then added and blended for a further 2minutes at 6 rpm and finally the talc was added and blended for afurther 2 minutes at 6 rpm.

The blend was then compacted on a compactor (Bepex Pharmapaktor L 200/50P, Hosokawa Micron Ltd., UK). The compaction was performed in 2sub-batches of about 41 Kg for sub-batch 1 (batch no.: E341X043) andabout 56 kg for sub-batch 2 (batch no.: E341X044) using two differentsettings for the roller compression force to optimize the processparameter. Both compaction settings produced properly compactedmaterial. Table 12 lists the different settings.

TABLE 12 Compactor Settings Setting 1 Setting 2 Screw size 3 3 Screwrotation (rpm) 48 77 Roller compression force (kN) 29 35 Roller type(corrugated) 4.1 4.1 Roller rotation (rpm) 7.7 12.2 Sieve size (mm) 1.251.25 Sieve rotation (rpm) 56 77

Physical characteristics of the blend as shown in Table 13 weredetermined.

TABLE 13 Physical Characteristics of Final Blend Results Setting 1Results Setting 2 Method (E341X043) (E341X044) Bulk density Ph. Eur.2.9.15 1.000 0.980 Tapped density Ph. Eur. 2.9.15 1.282 1.250Hausner-ratio — 1.282 1.275 Particle Size Ph. Eur. 2.9.16 <63 μm 23.3%<63 μm 15.4% distribution 63-90 μm 11.9% 63-90 μm 10.6% 90-125 μm 9.8%90-125 μm 13.8% 125-250 μm 18.0% 125-250 μm 18.9% 250-500 μm 21.6%250-500 μm 23.0% 500-710 μm 11.7% 500-710 μm 12.3% 710-1000 μm 3.7%710-1000 μm 5.9% 1000-1250 μm 0.2% 1000-1250 μm 0.1% >1250 μm 0.0% >1250μm 0.0%

The material processed on setting 2 showed a lower amount of fineparticles which could be an advantage for the filing of capsules. Thereare no significant differences between Bulk and tapped density.

Both final blends in an amount equal to 500 mg elemental lanthanum werefilled into Coni-Snap® hard gelatine capsules size 00 (available fromCapsugel®, Peapack, N.J.) using a capsule filler (GKF 1500 or KKE 1500available from Bosch, Brooklyn Park, Minn.). For the purpose ofevaluation of process robustness, two different speeds for the fillerwere used (90 cycles/min and 100 cycles/min). The machine runs steadilywith both speeds but capsule filling runs more smoothly with compactionsetting 2 in comparison with compaction setting 1.

Example 11 Dissolution Testing of Lanthanum Carbonate CapsulesContaining Talc

The capsules (E341X043 and E341X044) were stored at room temperature andin stressed conditions in a drying oven at 60° C. for one week and weretested for their dissolution properties. The results are presented inTable 14 and FIG. 10.

TABLE 14 Tablet dissolution results for tablets stored at roomtemperature and at 60° C. for 1 week Dissolution Batch E341X043 BatchE341X044 time point Room One week Room One week [min] temperature at 60°C. temperature at 60° C. 5 79.8 82.2 83.3 80.7 10 89.2 89.6 91.6 91.4 1594.6 93.7 95.3 95.2 30 96.8 96.0 97.6 97.4 45 98.6 98.4 99.2 98.8

All dissolution profiles fulfilled the specification of greater than 80%lanthanum carbonate dissolution after 30 minutes. A decreasing of thedissolution rate after storage for one week at 60° C. in comparison withroom temperature was not evident. The results showed no significantdifference between the two batches. The results showed that the talc canbe used as lubricant for manufacturing of lanthanum carbonate capsuleswith no significant effect on the dissolution rate compared to thestorage condition.

Example 12 Long Term Stability Testing of Lanthanum Carbonate 500 mgCapsules

Capsules were manufactured according to Example 10 and placed on a longterm stability test. Table 15 provides stability data after 4 weeks.

TABLE 15 Stability Data for Lanthanum Carbonate 500 mg Capsules; Lot1005001; 200 mL HDPE Bottle with Polypropylene Closure, 90 CountLanthanum Hydroxycarbonate Storage Lanthanum Moisture PolymorphDissolution Time Appearance Assay (%) (% w/w) Polymorph I II (%)Specification Hard gelatin 90-110% Record Not more Not more Q = 80%after 30 capsule with than 1.8% than 2.0% minutes opaque purple capprinted S405, opaque white body printed 500 mg and containing a white tooff- white granulate. Initial Complies 98.2 1.6 Complies Complies 97 25°C./60% RH 4 weeks Complies 99.5 1.7 Complies Complies 97 30° C./75% RH 4weeks Complies 99.4 1.6 Complies Complies 97 40° C./75% RH 4 weeksComplies 98.6 1.2 Complies Complies 95

Data showed no change or essentially no change in the percentdissolution after 30 minutes in 0.25 M HCl after storage at 25° C./60%RH, 30° C./75% RH, or 40° C./75% RH for 4 weeks. Capsules from thisbatch are used in a clinical study to evaluate the bioavailability oflanthanum carbonate from capsules relative to that from tablets.

Examples 13 and 14 Pharmacodynamic Equivalence Studies for LanthanumCarbonate for Formulations

These examples describe results from pharmacodynamic equivalence studiesto compare the delivery of lanthanum to and availability of lanthanum inthe gastrointestinal tract and its absorption into the systemiccirculation (blood plasma) from capsule or oral powder formulations withthose from the chewable tablet. These studies are conducted in healthyvolunteers who do not have elevated serum phosphate concentrations.Hence, the efficacy of lanthanum carbonate in reducing serum phosphateconcentrations, which would be the usual primary endpoint in a clinicalstudy in ESRD patients on dialysis, cannot be used in healthy volunteerstudies. Urinary phosphate excretion is an alternative measure which canbe used in healthy volunteers to assess the impact of a phosphate binderon phosphate absorption from a standard meal and this is the primaryendpoint in pharmacodynamic equivalence studies: the higher the urinaryphosphate excretion, the higher the extent of phosphate absorption.Hence the formulations are compared with respect to the extents of theireffects on urinary phosphate excretion, which are assessed againstequivalence acceptance criteria. In addition, plasma lanthanumconcentrations are compared as a secondary objective, since lanthanumsystemic exposure is a surrogate safety marker.

Example 13

A Phase 1 pharmacodynamic equivalence study comparing urinary phosphateexcretion and plasma lanthanum pharmacokinetics for a lanthanumcarbonate capsule formulation, a lanthanum carbonate opened capsuleformulation, and chewable lanthanum carbonate tablets administered tohealthy adult subjects

Objectives: Primary

To compare the average daily urinary phosphate excretion over 3 daysfollowing dosing between a lanthanum carbonate capsule formulation(Formulation A) and a lanthanum carbonate chewable tablet formulation(Formulation C), administered as 1000 mg 3 times per day withapple-sauce, immediately following meals.

Objectives: Secondary

(1) To compare the average daily urinary phosphate excretion over 3 daysfollowing dosing between lanthanum carbonate opened capsules(Formulation B) and lanthanum carbonate chewable tablet formulations(Formulation C). Each dose was administered as 1000 mg 3 times per daygiven with apple sauce immediately following meals

(2) To compare the urinary phosphate excretion on Day 4 following 3 daysof dosing of the lanthanum carbonate capsule formulation (FormulationA), the opened capsule formulation (Formulation B), and the chewabletablet formulation (Formulation C).

(3) To assess the safety and tolerability of the lanthanum carbonatecapsule formulation (Formulation A), the opened capsule formulation(Formulation B), and chewable tablet formulation (Formulation C).

(4) To compare the lanthanum pharmacokinetic (PK) profiles of thelanthanum carbonate capsule formulation (Formulation A) and the openedcapsule formulation (Formulation B) with the lanthanum carbonatechewable tablet formulation (Formulation C).

Study Design

A randomized, open-label, 3-period crossover study was performed inhealthy male and female volunteers (aged 18-55 years at the time ofconsent) conducted at a single study center. There was a screeningperiod followed by 3 dosing periods for each subject. There was awashout period of at least 14 days between dosing periods. Subject wererandomised to a dosing sequence where they received 1 of 3 formulationsin a random order:

(1) Formulation A, a capsule formulation (2×500 mg/capsules; Coni-Snap®hard gelatine capsules size 00 filled with the formulation of Table 11manufactured according to Example 10 using a compaction setting similarto Setting 2) in which subjects ingested 1 tablespoon of applesauceimmediately after taking each capsule (2 tablespoons of applesauce perdose).

(2) Formulation B, an open capsule formulation (2×500 mg/capsule; theformulation of Table 11 manufactured according to Example 10 using acompaction setting similar to Setting 2 without the capsule)administered by means of the capsule formulation being opened, thecontents of each capsule placed on 1 tablespoon of applesauce, theapplesauce and contents administered to the subject, and the emptygelatinous capsule discarded, and

(3) Formulation C, chewable tablet formulation (2×500 mg/tabletavailable as 500 mg Fosrenol® from Shire, Wayne, Pa. containing (1) 954mg lanthanum carbonate (45.78% wt/wt), (2) 1066.4 mg dextrates (51.17%wt/wt), (3) 42.4 mg colloidal silicon dioxide (2.03% wt/wt), and (4)21.2 mg magnesium stearate (1.02% wt/wt)) in which subjects alsoingested 1 tablespoon of applesauce immediately after taking each tablet(2 tablespoons of applesauce per dose).

Within each period, each formulation was administered 3 times per dayfollowing meals for 3 days and following the morning meal of day 4.There were three treatment periods, subjects were randomised to 1 of 6treatment sequences according to the randomization code, with a wash-outperiod of at least 14 days between periods.

Sufficient subjects were randomized to ensure a minimum of 72 subjectscompleted the study.

Criteria for Evaluation

Urine was collected over 24 hour periods as: Day −2 to Day −1; Day −1 toDay 1; Day 1 to Day 2; Day 2 to Day 3 and Day 3 to Day 4. Eachcollection started within 30 minutes before the morning meal and ended24 hours later. Urinary phosphate excretion analysis was the primaryevaluation for the determination of pharmacodynamic equivalence for thisstudy.

As a secondary evaluation, pharmacokinetic assessments were performedfollowing determination by inductively coupled plasma mass spectrometryof plasma concentrations of lanthanum at the following times: pre-dose(within 30 minutes prior to the start of the morning meal) on Days 1, 2,3 and 4 and at 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after thefinal morning dose on Day 4.

Statistical Methods: Pharmacodynamics

Subjects included in the safety population took at least one dose oflanthanum carbonate and had at least one post-dose safety assessment.The pharmacodynamic population included all evaluable subjects from thesafety population with no major protocol deviations, including allsubjects in the safety population who completed all urine collectionsand consumed at least 95% of food in all treatment periods. Subjects whovomited between days −2 and 4 in a dosing period were excluded.

The primary pharmacodynamic variable was the average daily urinaryphosphate excretion over 3 days in each dosing period. The variable wasassessed without transformation by using a mixed effect linear modelwith fixed effects for treatment sequence, dosing period andformulation, random effect for subject-within-sequence group, and periodbaseline as a covariate. The baseline measure was the average of totalurinary phosphate excretion on Day −1 and Day 1 from each period. Basedon the mixed effect linear model, a standard 90% confidence interval(CI) was constructed for the difference in least squares (LS) means ofthe primary pharmacodynamic variable between test Formulation A(capsule) and reference Formulation C (chewable tablet) and between testFormulation B (opened capsule) and reference Formulation C (chewabletablet). In addition, a reference interval representing ±20% of the LSmean (i.e. ±LS least squares means*20%) of the reference Formulation Cwas constructed. Pharmacodynamic equivalence was claimed if the 90% CIfor the difference (A−C or B−C) was completely contained within thereference interval.

Subjects who provided non-quantifiable urine concentrations wereincluded in the Pharmacodynamic Set by setting non-quantifiable valuesto 1.5; half the lower limit of detection of the assay.

The secondary pharmacodynamic variable was the urinary phosphateexcretion on Day 4 (i.e., Day 3 to Day 4) and was assessed using thesame model as for the primary variable.

Urinary phosphate excretion and change from baseline were summarized byformation using descriptive statistics (number of observations [n],mean, standard error [SE], coefficient of variation [CV %], median,minimum, and maximum).

Statistical Methods: Pharmacokinetics

The pharmacokinetic population included subjects from the safetypopulation with no major deviations related to intake of lanthanumcarbonate, including all subjects in the safety population withsufficient post-dose blood samples taken to estimate C_(max) and AUC₀₋₄₈after dosing on day 4 in all treatment periods. Subjects who vomitedbetween dosing and 10 hours post-dose on day 4 of a dosing period wereexcluded from the pharmacokinetic population.

The PK analysis included C_(max), t_(max), AUC_(0-t), AUC₀₋₄₈, λ_(z),and t_(1/2), where

-   -   C_(max): Maximum plasma concentration    -   t_(max): Time to C_(max)    -   AUC₀₋₄₈: Area under the plasma concentration-time curve from        time zero to 48 hours after dosing on Day 4    -   AUC_(0-t): Area under the plasma concentration-time curve from        time zero to time (t) of the last quantifiable plasma        concentration (Ct)    -   λ_(z): Apparent terminal phase rate constant    -   t_(1/2): Apparent terminal half-life.

Descriptive statistics (number of subjects, mean, standard deviation(SD), CV %, geometric mean, median, maximum, and minimum) weredetermined for the pharmacokinetic parameters of lanthanum. Thepharmacokinetic parameters C_(max), AUC₀₋₄₈ and AUC_(0-t) of lanthanumwere analyzed after logarithmic transformation using a standard mixedeffect linear model. From the LS mean and SE of the difference (A−C), a90% CI was constructed for the difference of the logs of A and B. Toreturn to the original scale, an exponential transformation was appliedto the lower and upper limits of the CI. This created a point estimateand 90% CI for the ratio of LS means for Formulation A to Formulation CIn addition, t_(max) was compared between formulations using theWilcoxon signed rank test. The same models were used to compareFormulation B with Formulation C.

Results

Subject Disposition

Subject disposition is presented in Table 16.

TABLE 16 Number of subjects (planned and analysed) Overall Enrolledsubjects - n 96 Randomized subjects - n  96 (100.0) Safety set - n (%) 96 (100.0) Pharmacodynamic set - n (%) 92 (95.8) Pharmacokinetic set -n (%) 91 (94.8) Completed the study - n (%) 91 (94.8) Did not completethe study - n (%) 5 (5.2)Pharmacodynamic Results

Table 17 presents the results of the pharmacodynamic analysis of the3-day average of urinary phosphate excretion comparing capsules vs.chewable tablets and open capsules vs. chewable tablets. To concludepharmacodynamic equivalence, the 90% CI must be contained within theCritical Reference Interval.

TABLE 17 The 3-day average of urinary phosphate excretion comparingcapsules vs. chewable tablets and open capsules vs. chewable tablets.Capsule (A) Open Capsule (B) Chewable Tablet (C) (N = 92) (N = 92) (N =92) Baseline Mean (SE) 26.10 (0.617) 26.22 (0.654) 26.37 (0.714) Min,Max 14.3, 40.9 12.3, 41.4 10.0, 42.8 Post-dose over 3 days Mean (SE)19.18 (0.626) 15.34 (0.525) 16.39 (0.615) Min, Max 6.9, 36.1 3.3, 25.9 2.6, 31.8 LS Mean (SE) 19.24 (0.427) 15.35 (0.427) 16.32 (0.427)Difference of the LS Means 2.92 −0.97 90% CI of the Difference (2.21,3.64) (−1.68, −0.25) Critical Reference Interval* (−3.26, 3.26) *±20%LSMean of reference Formulation C (chewable tablet)

Mean average urinary phosphate excretion reduced from a baseline of26.10 mmol to 19.18 mmol for the capsule treatment and from a baselineof 26.37 mmol to 16.39 mmol for the chewable tablets treatment. The 90%CI of the difference was not entirely contained within the criticalreference range and so pharmacodynamic equivalence between the lanthanumcarbonate capsules and FOSRENOL® chewable tablets could not therefore beclaimed.

In contrast, lanthanum carbonate opened capsules were shown to bepharmacodynamically equivalent to FOSRENOL® chewable tablets. Meanaverage urinary phosphate excretion reduced from a baseline of 26.22mmol to 15.34 mmol for the opened capsules treatment and from a baselineof 26.37 mmol to 16.39 mmol for the chewable tablets treatment. The 90%CI of the difference was wholly contained within the critical referenceinterval.

Table 18 is a pharmacodynamic analysis of Day 4 urinary phosphateexcretion comparing capsules vs. chewable tablets and open capsules vs.chewable tablets. In addition, a reference interval representing ±20% ofthe reference Formulation C LS mean was constructed.

TABLE 18 The Day 4 urinary phosphate excretion comparing capsules vs.chewable tablets and open capsules vs. chewable tablets. Capsule (A)Open Capsule (B) Chewable Tablet (C) (N = 92) (N = 92) (N = 92) BaselineMean (SE) 26.10 (0.617) 26.22 (0.654) 26.37 (0.714) Min, Max 14.3, 40.912.3, 41.4 10.0, 42.8 Post-dose at Day 4 Mean (SE) 17.19 (0.666) 13.77(0.627) 14.37 (0.721) Min, Max 6.2, 33.3 1.8, 29.2  2.5, 36.9 LS Mean(SE) 17.24 (0.563) 13.78 (0.563) 14.31 (0.563) Difference of the LSMeans 2.93 −0.53 90% CI of the Difference (1.90, 3.96) (−1.56, 0.50)Critical Reference Interval* (−2.86, 2.86) *±20% LSMean of referenceFormulation C (chewable tablet)

Results for Day 4 urinary phosphate excretion were consistent with thosefor the 3-day average urinary phosphate excretion, with the 90%Confidence Interval of the difference was not entirely contained withinthe Critical Reference Interval for the capsule, but being whollycontained within this interval for the opened capsule.

Pharmacokinetic Results

FIG. 11 presents a graph displaying the mean plasma concentrations oflanthanum on Day 4 after oral administration of multiple tid doses oflanthanum carbonate as Regimen A (2×500 mg capsules), Regimen B (2×500mg opened capsules), or Regimen C (2×500 mg chewable tablets). Table 19is a summary of the PK parameters for these plasma concentrations oflanthanum. Table 20 is an analysis of the plasma lanthanumbioavailability parameters comparing the lanthanum carbonate capsules(Formulation A) and the lanthanum carbonate chewable tablets(Formulation C). Table 21 is an analysis of the plasma lanthanumbioavailability parameters comparing the lanthanum carbonate openedcapsules (Formulation B) and the lanthanum carbonate chewable tablets(Formulation C).

TABLE 19 A summary of the PK parameters derived from the plasmaconcentrations of lanthanum Capsule Opened Capsule Chewable TabletAUC₀₋₄₈ ^(a) 10.7 ± 6.13 14.2 ± 7.24 14.0 ± 6.44 C_(max) ^(a) 0.450 ±0.288 0.609 ± 0.355 0.573 ± 0.292 t_(max) ^(b) 3.00 3.00 3.00(0.00-12.0) (0.00-8.00) (0.00-12.0) ^(a) Mean ± SD; ^(b) Median (Range)

The AUC_(0-t) was not reported because it was identical to AUC₀₋₄₈(plasma lanthanum quantifiable in all subjects up to 48 hours afterdosing of all formulations).

TABLE 20 Analysis of plasma lanthanum bioavailability parameterscomparing Formulation A (Lanthanum Carbonate Capsules) and C (LanthanumCarbonate Chewable Tablets) Geometric Least Squares Means LanthanumCarbonate Lanthanum Carbonate Capsules Chewable Tablets Ratio 90% CI forParameter (Formulation A) (Formulation C) of A:C Ratio AUC₀₋₄₈ 9.37 12.60.742 (0.703, 0784) (ng · h/mL) C_(max) (ng/mL) 0.387 0.509 0.761(0.711, 0.814) t_(max) ^(a) 3 3 0 (0, 0.500) ^(a)Median, mediandifference (90% CI for median difference)

The AUC_(0-t) was not reported because it was identical to AUC₀₋₄₈(plasma lanthanum quantifiable in all subjects up to 48 hours afterdosing of all formulations).

TABLE 21 Analysis of plasma lanthanum bioavailability parameterscomparing Formulation B (Lanthanum Carbonate Opened Capsules) and C(Lanthanum Carbonate Chewable Tablets) Geometric Least Squares MeansLanthanum Carbonate Lanthanum Carbonate Opened Capsules Chewable Tablets90% CI for Parameter (Formulation B) (Formulation C) Ratio of B:C RatioAUC₀₋₄₈ 12.7 12.6 1.00 (0.950, 1.06) (ng · h/mL) C_(max) (ng/mL) 0.5230.509 1.03 (0.960, 1.10) t_(max) ^(a) 3 3 0 (−0.500, 0) ^(a)Median,median difference (90% CI for median difference)

The AUC_(0-t) was not reported because it was identical to AUC₀₋₄₈(plasma lanthanum quantifiable in all subjects up to 48 hours afterdosing of all formulations).

Systemic exposure to lanthanum was, on average, approximately 25% lowerfor the capsule than for the chewable tablet, based on the mean ratio(A:C) for AUC₀₋₄₈ and C_(max). However, on the same basis, the openedcapsule was found to deliver similar lanthanum systemic exposure to thatfor the chewable tablet.

Safety Results

There were no deaths or other serious adverse events (SAEs). Twosubjects discontinued the study due to AEs, 1 of which (allergicdermatitis) was treatment-emergent. The incidence of TEAEs was slightlyhigher after administration of lanthanum carbonate chewable tablets (13subjects, 13.8%) as compared to the capsules (6 subjects, 6.5%) andopened capsules (8 subjects, 8.5%) formulations. The most common TEAEswere nausea and headache (both 7 subjects, 7.3% overall) andconstipation (6 subjects, 6.3% overall).

Table 22 is a summary of the gastrointestinal (GI) treatment-emergentadverse events safety set.

TABLE 22 A summary of the GI treatment-emergent adverse events (SafetySet) Formulation Formulation Formulation B C A (Open (Chewable (Capsule)Capsule) Tablet) System Organ (N = 93) (N = 94) (N = 94) Overall (N =96) Class Subjects Events Subjects Events Subjects Events SubjectsEvents Preferred Term n (%) n n (%) n n (%) n n (%) n Any Adverse 6(6.5) 7 8 (8.5) 9 13 (13.8) 17 24 (25.0) 33 Event Gastrointestinal 4(4.3) 4 2 (2.1) 2 8 (8.5) 8 14 (14.6) 14 disorders Constipation 1 (1.1)1 2 (2.1) 2 3 (3.2) 3 6 (6.3) 6 Diarrhoea 0 (0.0) 0 0 (0.0) 0 1 (1.1) 11 (1.0) 1 Nausea 3 (3.2) 3 0 (0.0) 0 4 (4.3) 4 7 (7.3) 7Summary and Conclusions

Lanthanum carbonate capsules were found not to be pharmacodynamicallyequivalent to lanthanum carbonate chewable tablets. However, lanthanumcarbonate opened capsules were found to be pharmacodynamicallyequivalent to lanthanum carbonate chewable tablets.

Based on the statistical analysis of AUC₀₋₄₈ and C_(max), plasmalanthanum concentrations were approximately 25% lower for the capsulethan for the chewable tablet while plasma lanthanum concentrations weresimilar for the opened capsule and for the chewable tablet. The rate ofabsorption of lanthanum was also lower from the capsules than from thechewable tablet formulation, based on achievement of a lower C_(max)value for the capsules at the same median t_(max) as that for thechewable tablet. Overall, lanthanum carbonate capsules (intact andopened) and lanthanum carbonate chewable tablets were well tolerated.There was no clinically relevant difference between the groups in any ofthe safety parameters assessed.

Example 14

A Phase 1 pharmacodynamic equivalence study comparing urinary phosphateexcretion and plasma lanthanum pharmacokinetics for a lanthanumcarbonate granule* formulation and lanthanum carbonate chewable tabletsadministered to healthy adult subjects *subsequently known as oralpowder

Objectives: Primary

To compare the average daily urinary phosphate excretion over 3 daysfollowing dosing between a lanthanum carbonate granules formulation(formulation A) and lanthanum carbonate chewable tablets (formulationB), administered as 1000 mg 3 times per day with apple-sauce,immediately following meals.

Objectives: Secondary

(1) To compare urinary phosphate excretion on Day 4 following 3 days ofdosing with a lanthanum carbonate granules formulation (formulation A)and lanthanum carbonate chewable tablets (formulation B)

(2) To assess the safety and tolerability of a lanthanum carbonategranules formulation (formulation A) with lanthanum carbonate chewabletablets (formulation B)

(3) To compare the lanthanum phannacokinetic profiles of a lanthanumcarbonate granules formulation (formulation A) with lanthanum carbonatechewable tablets (formulation B).

Study Design

This was a randomized, open-label, 2-period, cross-over study in healthymale and female volunteers (aged 18-55 years at the time of consent)conducted at a single study center. There was a screening periodfollowed by 2 dosing periods for each subject. Subjects were dosed witheither granules formulation A or the reference chewable tabletformulation B according to their randomization during each study period.There was a washout period of at least 14 days between dosing periods.

For formulation A (containing 68.14 wt % lanthanum carbonatetetrahydrate, 30.56 wt % dextrates (hydrated), 1.0 wt % colloidalsilicon dioxide, and 0.3 wt % magnesium stearate, batch number: 807012),subjects received 1 lanthanum carbonate granules sachet (1000 mg/dose)after meals 3 times daily for 3 days followed by a single granulessachet (1000 mg) on Day 4, administered immediately following breakfast.Each dose was administered sprinkled on 1 tablespoon of apple sauce.

For formulation B (lanthanum carbonate available as Fosrenol® fromShire, Wayne, Pa. containing the same percentages of ingredients asFormulation C of Example 13, batch number: A38683B), subjects received 1chewable tablet of FOSRENOL® (1×1000 mg/tablet) after meals, 3 timesdaily for 3 days followed by a single dose on Day 4 immediatelyfollowing breakfast. Subjects received 1 chewable tablet and thenimmediately ingested 1 tablespoon of apple sauce after taking thetablet.

Sufficient subjects were randomized to ensure a minimum of 46 subjectscompleted the study.

Criteria for Evaluation

Urine was collected over 24 hour periods as: Day −2 to Day −1; Day −1 toDay 1; Day 1 to Day 2; Day 2 to Day 3 and Day 3 to Day 4. Eachcollection started with 30 minutes before the morning meal and ended 24hours later. Urinary phosphate excretion analysis was the primaryevaluation for the determination of pharmacodynamic equivalence for thisstudy.

As a secondary evaluation, pharmacokinetic assessments were performed byinductively coupled plasma mass spectrometry following determination ofplasma concentrations of lanthanum at the following times: pre-dose(within 30 minutes prior to the start of the morning meal) on Days 1, 2,3 and 4 and at 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours after thefinal morning dose on Day 4.

Statistical Methods: Pharmacodynamics

Subjects included in the safety population took at least one dose oflanthanum carbonate and had at least one post-dose safety assessment.The pharmacodynamic population included all evaluable subjects from thesafety population with no major protocol deviations, including allsubjects in the safety population who completed all urine collectionsand consumed at least 95% of food in all treatment periods. Subjects whovomited between days −2 and 4 in a dosing period were excluded.

The primary pharmacodynamic variable was the average daily urinaryphosphate excretion over 3 days in each dosing period. The variable wasassessed without transformation by using a mixed effect linear modelwith fixed effects for treatment sequence, dosing period andformulation, random effect for subject-within-sequence group, and periodbaseline as a covariate. The baseline measure was the average of totalurinary phosphate excretion on Day −1 and Day 1 from each period. Basedon the mixed effect linear model, a standard 90% confidence interval(CI) was constructed for the difference in least squares (LS) means ofthe primary pharmacodynamic variable between test formulation A(granules) and reference formulation B (chewable tablet). In addition, areference interval representing ±20% of the reference formulation B LSmean (i.e. ±LS least squares means*20%) was constructed. Pharmacodynamicequivalence was claimed if the 90% CI for the difference (A−B) wascompletely contained within the reference interval.

Subjects who provided non-quantifiable urine concentrations wereincluded in the Pharmacodynamic Set by setting non-quantifiable valuesto 1.5; half the lower limit of detection of the assay.

The secondary pharmacodynamic variable was assessed by using a mixedeffect linear model with fixed effects for sequence group, period andformulations, random effect for subject within sequence group, andperiod baseline as a covariate. Based on the mixed effect linear model,a standard 90% CI was constructed for the difference in LS means of thesecondary pharmacodynamic variable between test formulation A andreference formulation B. In addition, a reference interval representing±20% of the reference formulation B LS mean was constructed.

Urinary phosphate excretion and change from baseline were summarized byformulation using descriptive statistics (number of observations [n],mean, standard error [SE], coefficient of variation [CV %], median,minimum, and maximum).

Statistical Methods: Pharmacokinetics

The pharmacokinetic population included subjects from the safetypopulation with no major deviations related to intake of lanthanumcarbonate, including all subjects in the safety population withsufficient post-dose blood samples taken to estimate C_(max) and AUC₀₋₄₈after dosing on day 4 in all treatment periods. Subjects who vomitedbetween dosing and 10 hours post-dose on day 4 of a dosing period wereexcluded from the pharmacokinetic population.

The PK analysis included C_(max), t_(max), AUC_(0-t), AUC₀₋₄₈, λ_(z),and t_(1/2), where the means of these terms are the same as in Example13. Descriptive statistics (number of subjects, mean, standard deviation(SD), CV %, geometric mean, median, maximum, and minimum) weredetermined for the pharmacokinetic parameters of lanthanum. Thepharmacokinetic parameters C_(max), AUC₀₋₄₈ and AUC_(0-t) of lanthanumwere analyzed after logarithmic transformation using a standard mixedeffect linear model. From the LS mean and SE of the difference (A−B), a90% CI was constructed for the difference of the logs of A and B. Toreturn to the original scale, an exponential transformation was appliedto the lower and upper limits of the CI. This created a point estimateand 90% CI for the ratio of LS means for Formulation A to Formulation B.In addition, t_(max) was compared between formulations using theWilcoxon signed rank test.

Results

Subject Disposition

Subject disposition is presented in Table 23.

TABLE 23 Number of subjects (planned and analyzed) Overall (N = 72)Enrolled subjects - n 72 Randomized subjects - n 72 Safety set - n (%) 72 (100.0) Pharmacodynamic set - n (%) 53 (73.6) Pharmacokinetic set -n (%) 64 (88.9) Completed the study - n (%) 56 (77.8) Did not completethe study - n (%) 16 (22.2)Pharmacodynamic Results

Table 24 presents the results of the pharmacodynamic analysis of the3-day average of urinary phosphate excretion comparing granules andchewable tablets.

TABLE 24 Analysis of 3-Day Average of Urinary Phosphate Excretion A(Granules) B (Chewable Tablet) N = 53 N = 53 Average Daily UrinaryPhosphate Excretion (mmol) Baseline Mean (SE) 30.63 (0.865) 29.43(0.876) Min, Max 14.99, 43.95 18.27, 42.79 Post-dose over 3 Days Mean(SE) 15.28 (0.565) 16.57 (0.602) Coefficient of Variation (%) 26.93726.468 Median 15.15 16.25 Min, Max 3.76, 23.22 7.81, 25.05 LS Mean (SE)15.16 (0.477) 16.76 (0.476) Difference of the LS Means^(b) −1.60 90% CIof the Difference (−2.38, −0.82) Critical Reference Interval * (−3.35,3.35) * ±20% of the reference formulation B LS mean.

The primary analysis of 3 day average urinary phosphate excretiondemonstrated lanthanum carbonate granules to be pharmacodynamicallyequivalent to FOSRENOL® chewable tablets. Mean average urinary phosphateexcretion reduced from a baseline of 30.63 mmol to 15.28 mmol for thegranules treatment and from a baseline of 29.43 mmol to 16.57 mmol forthe chewable tablets treatment. The 90% CI of the difference wasentirely contained within the critical reference interval.

Table 25 is a pharmacodynamic analysis of Day 4 urinary phosphateexcretion comparing granules and chewable tablets.

TABLE 25 Analysis of Day 4 Urinary Phosphate Excretion A (Granules) B(Chewable Tablet) N = 53 N = 53 Day 4 Urinary Phosphate Excretion (mmol)Baseline Mean (SE) 30.63 (0.865) 29.43 (0.876) Min, Max 14.99, 43.9518.27, 42.79 Day 4 Mean (SE) 14.49 (0.644) 15.86 (0.712) Min, Max 3.78,23.91 3.21, 30.61 LS Mean (SE) 14.39 (0.617) 16.05 (0.616) Difference ofthe LS Means −1.66 90% CI of the Difference (−2.85, −0.48) CriticalReference* (−3.21, 3.21) *±20% of the reference formulation B LS mean.

The secondary analysis of urinary phosphate excretion on Day 4 supportedthe finding of the primary analysis. Mean average urinary phosphateexcretion reduced from a baseline of 30.63 mmol to 14.49 mmol for thegranules treatment and from a baseline of 29.43 mmol to 15.86 mmol forthe chewable tablets treatment. Again, the 90% CI of the difference wasentirely contained within the critical reference interval.

Pharmacokinetic Results

FIG. 12 presents a graph displaying the mean plasma concentrations oflanthanum on Day 4 after oral administration of multiple tid doses oflanthanum carbonate as Regimen A (1000 mg granules) or Regimen B (1000mg chewable tablets). Table 26 is a summary of the PK parameters forthese plasma concentrations of lanthanum. Table 27 is an analysis of theplasma lanthanum bioavailability parameters comparing the lanthanumcarbonate granules (Formulation A) and the lanthanum carbonate chewabletablets (Formulation B).

The pharmacokinetic parameters of lanthanum and associated statisticalanalysis, following administration of the final dose of lanthanumcarbonate granules and lanthanum carbonate chewable tablets, arepresented in Tables 26 and 27, respectively.

TABLE 26 The pharmacokinetic parameters of lanthanum in plasma followingadministration of the final dose of lanthanum carbonate granules andlanthanum carbonate chewable tablets Lanthanum carbonate Lanthanumcarbonate granules chewable tablets (Formulation A) (Formulation B)Parameter (N = 64) (N = 58) AUC₀₋₄₈ 14.2^(b) (6.02) 10.3 (3.50) (ng ·h/mL) C_(max) (ng/mL) 0.638 (0.241) 0.504 (0.181) t_(max) ^(a) (h) 4.00(0-6.00) 4.00 (0-8.00) t_(1/2) (h) 21.9^(c) (2.96) 22.3^(d) (3.37)Arithmetic mean (SD) data are presented N = Number of subjects^(a)Median (min-max) ^(b)N = 62, ^(c)N = 28 ^(d)N = 23

TABLE 27 The pharmacokinetic parameters and statistical analysis oflanthanum in plasma following administration of the final dose oflanthanum carbonate granules and lanthanum carbonate chewable tabletsGeometric least squares (LS) means Lanthanum Lanthanum Ratio ofcarbonate carbonate geometric LS granules chewable tablets means (90%CI) Parameter (Formulation A) (Formulation B) (A:B) AUC₀₋₄₈ 13.11 9.801.34 (1.26, 1.42) (ng · h/mL) AUC_(0-t) 13.11 9.80 1.34 (1.26, 1.42) (ng· h/mL) C_(max) (ng/mL) 0.60 0.47 1.26 (1.20, 1.33) t_(max) ^(a) (h) 4 40.01 (0.00, 0.50) ^(a)Median, Median difference (90% CI) (A − B) onuntransformed data.

Systemic exposure to lanthanum was higher for the granules than for thechewable tablet, approximately 30% based on the ratios (A:B) for AUC₀₋₄₈and C_(max), and was more variable.

Safety Results

There were no deaths or other serious adverse events (SAEs). One subjectdeveloped treatment-emergent adverse events (TEAEs) leading todiscontinuation (abdominal distension and vomiting). The adverse eventswere judged by the investigator to be unrelated to study medication.

The incidence of TEAEs was higher after the administration of thegranules formulation (23 subjects, 32.4%) than after chewable tablets(14 subjects, 23.0%). The difference between the groups with regard tothe incidence of TEAEs was largely attributable to gastrointestinaldisorders (13 subjects, 18.3% granules formulation and 4 subjects, 6.6%chewable tablets), which comprised the system organ class most commonlyassociated with TEAEs. Table 28 is a summary of the gastrointestinal(GI) treatment-emergent adverse events safety set.

TABLE 28 Summary of TEAEs in the Gastrointestinal System Organ Class B(Chewable A (Granules) Tablet) Overall N = 71 N = 61 N = 72 n (%) eventsn (%) events n (%) events Gastro- 13 (18.3) 19 4 (6.6) 5 15 (20.8) 24intestinal disorders Nausea 6 (8.5) 7 3 (4.9) 3  8 (11.1) 10 Ab- 3 (4.2)3 1 (1.6) 1 3 (4.2) 4 dominal pain upper Dyspepsia 2 (2.8) 2 0 0 2 (2.8)2 Ab- 1 (1.4) 1 0 0 1 (1.4) 1 dominal discomfort Ab- 1 (1.4) 1 0 0 1(1.4) 1 dominal distension Ab- 1 (1.4) 1 0 0 1 (1.4) 1 dominal painCons- 1 (1.4) 1 0 0 1 (1.4) 1 tipation Diarrhea 1 (1.4) 1 0 0 1 (1.4) 1Dry mouth 0 0 1 (1.6) 1 1 (1.4) 1 Epigastric 1 (1.4) 1 0 0 1 (1.4) 1discomfort Vomiting 1 (1.4) 1 0 0 1 (1.4) 1 Note: AEs were coded usingthe MedDRA 12.0 AE dictionary. Note: Percentages are based on the numberof subjects in the Safety Set. Note: AEs were consideredtreatment-emergent if they occurred at or after the first dose of studymedication; or were present prior to the first dose but worsened inseverity; and up to and including Day 6 or discharge day for eachperiod.

The most common TEAEs were nausea (6 subjects, 8.5% granules formulationand 3 subjects, 4.9% chewable tablets) and headache (4 subjects, 5.6%granules formulation and 3 subjects, 4.9% chewable tablets). There was aslightly higher incidence of TEAEs judged by the investigator to betreatment-related in the granules group (14 subjects, 19.7%) as comparedto the chewable tablets (8 subjects, 13.1%). Most TEAEs were mild andtransient, and no subjects experienced a severe TEAE.

There were no clinically relevant findings in the clinical laboratorytests, physical examination, vital signs or 12-lead ECG results.

Summary and Conclusions

Lanthanum carbonate granules were found to be pharmacodynamicallyequivalent to FOSRENOL® chewable tablets.

The systemic exposure to lanthanum (based on AUC₀₋₄₈ and C_(max)) wasapproximately 30% higher and more variable following administration oflanthanum carbonate granules than following administration of lanthanumcarbonate chewable tablets. The rate of absorption of lanthanum was alsogreater from the granules formulation than from the chewable tablet,based on achievement of a higher C_(max) value for the granules at thesame median t_(max) as that for the tablet.

Based on what is known regarding the pharmacokinetic variability,toxicity, accumulation and excretion of lanthanum, this approximately30% increase in AUC₀₋₄₈ and C_(max) following granules administration isnot expected to have any clinical relevance or to alter the overall riskprofile of lanthanum carbonate granules formulation compared to thechewable tablet.

Overall, both lanthanum carbonate formulations were well-tolerated. Themodest differences between the treatment groups with regard to theincidence of gastrointestinal events was well within the variation seenin the FOSRENOL® Phase 1 program and is unlikely to be of clinicalrelevance.

Example 15 The Manufacture of Stick Packs Containing 500 mg or 1000 mgElemental Lanthanum as Lanthanum Carbonate in a Powder

This Example demonstrates the fill ability of capsule contents to befilled into stick packs instead of capsules. The powder capsule contentswere packaged at two filling weights corresponding to 500 mg and 1000 mgelemental lanthanum as lanthanum carbonate.

Manufacturing of Final Granules

The manufacturing process for the powder was performed at a batch sizeof 110 kg. Table 29 shows the formulation and the batch numbers ofingredients:

TABLE 29 Powder formulation ingredients Ingredient Batch Amount (kg) %(wt/wt) Lanthanum carbonate 3011914 95.400 86.7 Dextrates 3301606 9.07258.2 Colloidal silicon dioxide 3314396 1.100 1.0 Crospovidone 26073204.400 4.0 Talc 2248128 0.0275 0.025

The ingredients were weighed and sieved with a 1 mm hand sieve.Lanthanum carbonate, dextrates and crospovidone were blended for 40 minon a tumble blender (available from Servolift®, Wharton, N.J.) at 6 rpm.Afterwards, colloidal silicon dioxide and talc were added and blendedfor a further 5 minutes at 6 rpm. The final blend was compacted on aroller compactor and granules broken with a 1.25 mm sieve. Powder wasblended on a Servolift® tumble blender for 5 minutes at 6 rpm.

The process parameters are listed in Table 30:

TABLE 30 Process parameters of final powders Manufacturing stepparameter result Pre-blend Rotation speed [rpm] 6 Time [min] 40 Finalblend Rotation speed [rpm] 6 Time [min] 5 Roller compaction Screwrotation [rpm] 67 Screw size 3 Roller rotation [rpm] 11.0 Compressionforce [kN] 35 Roller type corrugated Sieve rotation [rpm] 75 Sieve size[mm] 1.25 Temperature [° C.] 18.3-21.5

A sample of powder was taken for measurement of particle sizedistribution and density. The results are listed in Table 31:

TABLE 31 Physical characteristics of final blend method results Bulkdensity Ph. Eur. 2.9.15 1.087 g/ml Tapped density Ph. Eur. 2.9.15 1.370g/ml Particle size Ph. Eur. 2.9.12 <63 μm 29.3% distribution 63-90 μm12.7% 90-125 μm 9.0% 125-250 μm 17.7% 250-500 μm 16.6% 500-710 μm 9.9%710-1000 μm 4.5% >1000 μm 0.3% D10 <90 μm 42.0% D50 <500 μm 85.3% D90<1000 μm 99.7%Stick Pack Filling Trials

The powders were filled into stick packs with two filling weightscorresponding to 500 mg and 1000 mg lanthanum as lanthanum carbonate.10,000 stick packs per dosage strength were filled as shown in Table 32.

TABLE 32 Stick pack filling strength filling weight stick pack size  500mg 1,100 mg 70 × 23 mm 1000 mg 2,200 mg 70 × 23 mm

For stick pack filling, unprinted laminate foil was used.

The packaging process was performed on stick pack line Merz SB51-1(available from Merz, Lich, Germany) by using the set up parameterslisted in Table 33:

TABLE 33 Packaging parameter for stick packs Parameter result Dosingauger [mm] 8 Heating length sealing [° C.] 115-120 Heating width sealing[° C.] 205-210 Heating FIN side [° C.] 105-115 Sealing pressure [bar]7.9-8.5 Auger speed [%] 60-70 Line speed [sticks/min] 40-60 Checkweighing balance [%] ±5

During packaging 100% check weighing and in process testing wasperformed to monitor the stick pack filling process. The results of thein process control testing are listed in Tables 34 and 35.

TABLE 34 In-process control results for the 1000 mg dosage strengthResult Result Result Test parameter 1 hour 2 hours 3 hours Appearance ofbulk Comply Comply Comply Sealing image Comply Comply Comply Tightnessvacuum test Comply Comply Comply Relative humidity (room) [%] 16 16 16Room temperature [° C.] 21 21 20 Mean weight [mg] 2178.4 2164.8 2174.4Weight variation (RSD) [%] 1.1 0.9 1.0 Waste (check weighing) [%] 2

TABLE 35 In-process control results for the 500 mg dosage strengthResult Result Result Result Result Test parameter 1 hour 2 hours 3 hours4 hours 5 hours Appearance of bulk Comply Comply Comply Comply ComplySealing image Comply Comply Comply Comply Comply Tightness vacuum testComply Comply Comply Comply Comply Rel. humidity (room) 15 15 16 16 16[%] Room temperature [° C.] 21 21 21 21 21 Mean weight [mg] 1,094.31,090.4 1,092.7 1,085.5 1,055.6 Weight variation (RSD) 2.3 1.5 2.7 1.72.2 [%] Waste (check weighing) 7 [%]

Stick pack filling process runs were very consistent without any issues.Waste and weight variations were higher during the packaging of the 500mg dosage strength caused by the lower fill weight of 1,100 mg. Forbatch sizes larger than 10,000 stick packs the percentage of waste,which is produced mainly during set up of the packaging line, will besignificantly lower. The fill weight of 2,200 mg for the 1000 mg dosagestrength showed no filling or sealing issues so the stick pack size of70×23 mm can be considered acceptable for both dosage strengths.

Analytical Testing of Final Stick Packs

Final testing on stick packs was performed according to the tests andspecifications listed in Table 36. The analytical results are listed inTables 36 and 37. All results comply with the current specification.

TABLE 36 Analytical testing for the 1000 mg stick packs Test:Specification Batch 3341481 Appearance of bulk white to off-whitegranules complies Mean Weight 2,200 mg ± 5% (2,090-2,310 mg) 2,190.40 mg(RSD 2.1%) Uniformity of complies Ph. Eur 2.9.40 98.78% Dosage Units n =10 AV 2.92 Lanthanum Assay 92.5-107.5% of label claim 99.03% (1000 mglanthanum) (98.9-99.1%)  Moisture (Karl for information only 1.13%Fischer) Dissolution complies Ph. Eur. 2.9.3 98.8% Lanthanum apparatus2, 50 rpm, 0.25 mol/L (97.5-100.3%) HCl Q 80% after 30 minutesdissolution

TABLE 37 Analytical testing for the 500 mg stick packs Test:Specification Batch 3341473 Appearance white to off-white granulescomplies Mean Weight 1,100 mg ± 5% (1,045-1,155 mg) 1,084.37 (RSD 2.7%)Uniformity of complies Ph. Eur. 2.9.40 99.39% Dosage Units n = 10 AV <15.0 AV 2.24 Lanthanum Assay 92.5-107.5% of label 99.15% claim (500 mg(99.1-99.2%) Lanthanum) Moisture (Karl for information only 1.15%Fischer) Dissolution complies Ph. Eur. 2.9.3 97.9% Lanthanum apparatus2, 50 rpm, 0.25 mol/L (96.0-99.2%) HCl Q 80% after 30 minutesdissolutionSummary

The stick pack filling of the lanthanum carbonate powder formulation wassuccessful. A stick pack size of 70×23 mm is acceptable for fillingpowder in a range of 1,100-2,200 mg corresponding to 500 mg-1000 mgelemental lanthanum as lanthanum carbonate.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will be apparent tothose skilled in the art from the foregoing description. Suchmodifications are intended to fall within the scope of the appendedclaims.

All references cited herein, including all patents, published patentapplications, and published scientific articles and books, areincorporated by reference in their entireties for all purposes.

The invention claimed is:
 1. An oral pharmaceutical powder comprising(1) lanthanum carbonate or lanthanum carbonate hydrate, (2)crospovidone, and (3) talc, wherein a plasma lanthanum concentration ofa patient after administration of the powder is similar to a plasmalanthanum concentration of the patient after administration of achewable tablet comprising lanthanum carbonate, dextrates, colloidalsilicon dioxide, and magnesium stearate.
 2. The powder of claim 1,wherein the lanthanum carbonate or lanthanum carbonate hydrate has theformula:La₂(CO₃)₃ .nH₂O wherein n has a value from 0 to
 10. 3. The powder ofclaim 2, wherein n has a value from 3 to
 6. 4. The powder of claim 1,wherein the lanthanum carbonate or lanthanum carbonate hydrate is in anamount from about 50% to about 95% by weight of the powder.
 5. Thepowder of claim 1, wherein the crospovidone is in an amount from about1.0% to about 15% by weight of the powder.
 6. The powder of claim 1,wherein the talc is in an amount from about 0.01% to about 0.05% byweight of the powder.
 7. The powder of claim 1, further comprising adiluent.
 8. The powder of claim 7, wherein the diluent is dextrates. 9.The powder of claim 7, wherein the diluent is in an amount from about 5%to about 50% by weight of the powder.
 10. The powder of claim 1, furthercomprising a flow aid.
 11. The powder of claim 10, wherein the flow aidis colloidal silicon dioxide.
 12. The powder of claim 10, wherein theflow aid is in an amount from about 0.1% to about 4.0% by weight of thepowder.
 13. The powder of claim 1 comprising (1) 86.7 wt % lanthanumcarbonate hydrate, (2) 8.2 wt % dextrates, (3) 1.0 wt % colloidalsilicon dioxide, (4) 4.0 wt % crospovidone, and (5) 0.025 wt % talc. 14.A method of treating hyperphosphatemia in a patient comprisingadministering to the patient an oral pharmaceutical powder comprising(1) lanthanum carbonate or lanthanum carbonate hydrate, (2)crospovidone, and (3) talc, wherein a plasma lanthanum concentration ofthe patient after administration of the powder is similar to a plasmalanthanum concentration of the patient after administration of achewable tablet comprising lanthanum carbonate, dextrates, colloidalsilicon dioxide, and magnesium stearate.
 15. A method of treating apatient (1) at risk of or suffering from chronic kidney disease (CKD),(2) at risk of or suffering from soft tissue calcification associatedwith chronic kidney disease (CKD), or (3) at risk of or suffering fromsecondary hyperparathyroidism comprising administering to the patient anoral pharmaceutical powder comprising (1) lanthanum carbonate orlanthanum carbonate hydrate, (2) crospovidone, and (3) talc, wherein aplasma lanthanum concentration of the patient after administration ofthe powder is similar to a plasma lanthanum concentration of the patientafter administration of a chewable tablet comprising lanthanumcarbonate, dextrates, colloidal silicon dioxide, and magnesium stearate.16. The method of claim 14, wherein the crospovidone is in an amountfrom about 1.0% to about 15% by weight of the powder.
 17. The method ofclaim 14, wherein the talc is in an amount from about 0.01% to about0.05% by weight of the powder.
 18. The method of claim 14, wherein thepowder further comprises a diluent.
 19. The method of claim 14, whereinthe powder further comprises a flow aid.
 20. The method of claim 14,wherein the powder comprises (1) 86.7 wt % lanthanum carbonate hydrate,(2) 8.2 wt % dextrates, (3) 1.0 wt % colloidal silicon dioxide, (4) 4.0wt % crospovidone, and (5) 0.025 wt % talc.